Skip to content

Xenobiotic Recognition Repertoires

May 30, 2012

This post is essentially the fourth part in continuation of the series ‘Subtle Environmental Poisons and Disease’, but in particular, it extends from the previous post dealing with xenorecognition, or the ability of organisms to recognize and contend with toxic chemicals ingested from the environment. Here we’ll focus on the range of xenobiotics which can be recognized by any of the different systems considered in the last post, which amounts to the biological recognition repertoire towards such chemicals. Is it complete, or can some chemical agents ‘fly under the radar’ and escape detection?

Recognizing xenobiotics

Failure of an organism’s defenses to recognize an incoming foreign compound would imply that its recognition range (or repertoire) was incomplete, such that its ability to ‘see’ certain molecules had one or more ‘holes’. While this is a logical proposition, it should be recalled that there are different levels of xenorecognition, including taste receptors, internal xenosensors, xenoprocessing enzymes, and xeno-exporters (considered in the previous post, see the relevant Figure . So, given that each level uses a different set of receptors, failure of recognition at one level has no necessary bearing on the potential recognition at other levels. The caveat ‘potential’ is used because in any linked functional chain, a breakdown at one stage will compromise later stages. (If an activation series A → B → C → D is absolutely dependent on the sequential input of each member, than obviously a ‘knock-out’ of A, B, or C will prevent the activation of D regardless of its intact state. D would then fail to be triggered unless alternative pathways for its activation existed). Thus, failure to activate a xenosensor may prevent effective upregulation of expression of the appropriate xenoprocessing enzymes (see the relevant Figure from the previous post), even if the latter are well-equipped to deal with the toxic threat. A hole in a repertoire in an ‘upstream’ defense level might therefore cause ineffective responses to a xenobiotic, even if the ‘downstream’ recognition repertoires are perfectly adequate.

On the other hand, some lines of defense might seem decoupled from others. At the frontline of molecular sensing, bitter taste receptors essentially warn ‘don’t eat this!’. Yet if a dangerous substance is eaten anyway, through either misadventure or failure to receive a bitter signal, then surely the next lines of defense would be independent of the breakdown in the first strategy of avoidance. True enough, given the apparent independent nature of taste perception relative to other xenosensing mechanisms, but an interesting wrinkle on this has emerged from observations that the T2R taste receptors (which transmit bitter signals) are also expressed in specific gut cells or airway smooth muscle cells. Obviously this does not involve direct sensory transmission, since we don’t experience taste signals through our intestines, despite many people often having a ‘gut feeling’ about all sorts of important matters. So what do these gut taste receptors do? Although much more work is required, recent results have suggested that they may have a role in limiting the gut-mediated absorption of potentially toxic molecules (defined as ‘bitter’ through their interaction with these receptors). If this is correct, taste receptors may have more than one role in limiting the intake of potentially noxious compounds.

In the context of poisons, it is possible to think of recognition in an inverted sense, since obviously any toxic substance must itself ‘recognize’ at least one type of physiological target, in order to exert any kind of toxic effect in the first place. This viewpoint strains the meaning of molecular recognition beyond its usual ‘recognition’, since at face value it would have to be inclusive of simple chemical reactivity between (for example) a toxic aldehyde group and many different proteins and other biomolecules. Yet it might be useful in passing simply as a backdrop for posing a hypothetical situation where a toxic substance ‘recognizes’ certain target molecules of an organism, but the organism’s defenses are completely blind to it, at all levels of xenorecognition. And taking this further still, what of molecules that do no harm at all, while likewise escaping recognition? Such ‘invisibility’ will be looked at a little more below.

Holes for the Individual, Holes for the Species

A second important issue with respect to holes in any biological receptor repertoire concerns individual variation versus the general repertoire for the species as a whole. Let’s look at this question once again with the first level of defense against xenobiotics, the taste receptors.

For over 80 years, it has been known that genetic differences in humans determine the taste response to certain defined simple chemical substances. For example, a substantial human fraction cannot experience the intensely bitter taste of the compound phenylthiourea (also known as phenylthiocarbamide, or PTC) reported by the remainder.  Over the last two decades, much has been learned about taste receptors, and the specific T2R receptor responsible for signaling PTC bitterness has been identified. Seven different alleles of this receptor have been identified, including the non-taster and major taster forms (the latter two being the only alleles occurring with substantial frequency outside sub-Saharan Africa). Interestingly, genetic evidence suggests that the non-taster allele has an ancient provenance, and this persistence has led to the proposal that it may have a selective benefit preserving it within the gene pool. This could have occurred if the non-taster receptor allele lost recognition for PTC but actually gained the ability to recognize and signal bitterness for some other (as yet unknown) naturally occurring compound. If both the taster and non-taster PTC alleles then provided fitness benefits under certain circumstances, both alleles would be preserved by ‘balancing’ natural selection.

Under such circumstances, the collective genotype of a species will be a mosaic of alternative alleles for sensing xenobiotics by taste. But in general, loss of sensory receptors can be a fitness gain if the sensory input no longer exists, or is no longer in any way beneficial, for the species. The classic example in this regard is the loss of sight (and eventually loss of complete eyes) in cave animals which live out their entire life-cycles in darkness. An interesting case in point with respect to chemical sensing is the loss of functional sweet taste receptors in domestic cats, which as obligate carnivores evidently have no need at all to experience sweetness or be attracted to sweet substances. Recently, this observation has been extended to a range of other ‘complete’ carnivores.  It is a well-understood evolutionary principle that unnecessary genetic function will tend to be lost, since individuals lacking such gene expression will gain a slight fitness advantage. This may well be at work in the evolution of ‘unsweet’ (though definitely not unsavory) carnivores, but it is possible that other factors which positively select for sweet taste loss also operate in these circumstances.

Yet where a single receptor has a degree of promiscuous ligand recognition, as with the bitter taste receptors, total ablation may always incur a fitness loss. (In a changing environment, some dangerous compounds recognized by such a receptor may no longer be encountered, but other compounds within the receptor’s individual recognition range may still be present). But a functional mutation in a receptor (rather than complete inactivation) might merely alter its specificity range, and could involve both losses and gains, as noted for the PTC story.

So in principle any xenosensory receptor could, through inactivating mutation, give rise to a specific repertoire reduction in an individual. This will constitute a fitness loss, and will be eliminated from naturally breeding populations even if the reduction in fitness is quantitatively very small. Selection in favor of loss (as with sweet taste in carnivores) is unlikely to ever occur with xenosensory receptors in general (including bitter taste receptors) for the reason of recognition promiscuity, but selection maintaining variation in individual receptor repertoires (as with PTC perception) is probably present. It should not be surprising that here we exclude sweet taste reception from xenosensing, since after all, the main targets of sweet perception are simple sugars (in food sources) which are certainly not foreign to any living biosystems. Yet the sweet taste receptor can definitely be triggered by completely non-natural compounds (saccharin, aspartame, and many others) and some intensely sweet natural proteins. This might be framed as ‘xenorecognition’ of a sort, but that is not the primary issue. It is the neurological end-point, the sensory perception at the end of the initial taste receptor triggering, which distinguishes a useful taste-mediated xenoreceptor. Sweet substances (naturally, in primate diets, mainly sugars in fruits) trigger a pleasurable response (‘good – eat me!’), while intensely bitter substances produce an aversive reaction (‘bad – don’t eat!) In fact, if a natural toxic substance elicited a sweet response, an animal might be stimulated to consume more of it, to its great detriment. And that of course would be completely contrary to everything that an effective xeno-response system should provide. Clearly, natural selection would rapidly change sweet taste receptors which acted in this way towards compounds in an animal’s normal environment, but no such selective pressures exist for substances which are never likely to be naturally encountered. An example of such an ‘unnatural’ toxic but sweet substance is ethylene glycol, widely used as an antifreeze. Poisonings of dogs and young children have been attributed to its sweetness, although hard evidence for this seems to be lacking. It is indisputable, though, that ethylene glycol is very toxic (through its metabolic products) and elicits a sweet taste. At very least, the perception of ethylene glycol sweetness would presumably not deter an animal with functioning sweet taste receptors from imbibing it, in the same way that a strongly bitter substance would.

While ‘holes’ in the xenobiotic recognition repertoire of a species as a whole could in principle occur at any level of xenosensing and processing (as noted above; see a Figure from the previous post), deficits in taste warning signals are relatively easy to define. So let’s consider an example of a general deficit of this kind towards an interesting group of highly toxic compounds.

Xeno-myopia to xeno-blindness?

Certain tropical marine fish can be source of a potent group of toxic compounds which upon consumption cause a condition known as ciguatera. The toxic principle involved, ciguatoxin, is a complex polyether chemically related to a number of other known marine poisons, including brevetoxin, palytoxin, and maitotoxin. (The latter is of interest as the largest natural bioproduct known, with a molecular weight of 3425 Daltons). Ciguatoxin itself exists as several chemical variants based on a common polyether skeleton, of molecular weights around 1000 –1100 Daltons. Polyether toxins are accumulated in fish through the food chain, with the original source identified as certain species of the marine eukaryotic single-celled protists known as dinoflagellates. (Although the ultimate synthetic machinery for synthesis of these large and complex molecules may come from symbiotic bacteria associated with specific dinoflagellate species).

Structure of a representative ciguatoxin, ciguatoxin-1. Letters A-M correspond to the nomenclature convention for each cyclic ether ring.


Unlike a great variety of plant-derived toxic alkaloids and other noxious molecular agents, ciguatoxin is tasteless, and thus fails to bind and activate any of the bitter taste receptors. But of course, failure to trigger the first line of defense has no bearing on what a molecule may do once ingested. The very high toxicity of ciguatoxin obviously demonstrates that it must very significantly interact with at least one physiological target. (In fact, it is neurotoxic, perturbing the activity of voltage-gated sodium and potassium channels which regulate nerve electrochemical transmission). While bypassing the frontline of taste, how is ciguatoxin ‘seen’ by the remainder of the xenosensory system? The metabolism of this compound (and related molecules) appears slow in experimental animals, with much ciguatoxin excreted in an unmodified state. Symptoms of ciguatera toxicity in humans can persist for months or even years following exposure, consistent with slow metabolic turn-over. On the other hand, evidence has been produced indicating that exposure of mice to ciguatoxin is associated with transcriptional activation of Phase I and II xenobiotic responses (phases of the latter responses were considered in the previous post).

In combination, these data would suggest that while ciguatoxin (and in turn other polyether marine toxins) can trigger xenobiotic sensors after its ingestion, its processing and removal from the body is not highly efficient. Certainly its lipid solubility may delay its removal, but that alone would not account for a very low level of metabolic processing. Given the focus of this post on xenorecognition repertoires, what is the limiting case of poor recognition of a toxic agent? In other words, if failure to taste ciguatoxin and its ensuing poor metabolism is ‘xeno-myopia’, is there any precedent for ‘xeno-blindness’, where a toxic agent creates havoc without any recognition or metabolic processing? Or would this be virtually a contradiction in terms? Given that xenorecognition operates by means of a specific set of receptors of limited number (albeit with considerable promiscuity) and a vast number of potential targets for a toxin exist in vivo, it might not seem an impossible prospect. Yet there seems to be no precedent for this. It is likely that certain compounds are indeed poor substrates for all metabolic processing enzymes (and thus slowly metabolized), but ‘poor’ is not at all the same as ‘invisible’. It may be the case that virtually all small molecules offer a weak binding site fit for the promiscuous pockets of at least some xenosensors and processing enzymes, allowing a slow level of  metabolic turnover. Alternatively, ‘non-specific’ attack by reactive oxygen species mught be a factor, noted again below.

In a xenobiotic context, the biological rationale for promiscuous recognition in the first place is to ensure that a limited number of receptors can cater for recognition of a much larger range of potential targets. But as with any biological issue. this question must also be considered from the perspective of evolutionary selective pressures. Evolutionarily speaking, the human species would have had little if any exposure to ciguatoxin until relatively very recent times, and even now, its impact is restricted to specific geographical areas. A maritime fish-eating species in tropical areas which was regularly threatened by ciguatera poisoning would be under a strong selective pressure to evolve a better xenorecognition system towards polyether toxins, including primary aversive taste sensitivity. Alternatively, evolution of means for very efficiently detoxifying or internally sequestering polyether toxins would allow otherwise contaminated marine foods to still serve as useful nutrient sources. (It is possible that some tropical fish have the latter kind of protection, since they can accumulate high levels of ciguatoxin without apparent ill-effects). Sometimes a small change in the amino acid sequence of a target molecule for a poison can make a very large difference in an agent’s toxicity. For example, consider the action of the insecticide DDT, which (in common with many of the polyether marine toxins) targets the neural voltage-gated sodium channel. It appears that only three key amino acid residue differences in the human vs, insect sodium channel determine the differential toxicity of DDT to insects. Selective pressures from environmental toxins could thus drive sequence changes in targets such as this voltage-gated channel, such that function is preserved but susceptibility to the toxin is diminished.

Xenosensing vs. adaptive immunity

While thinking about evolutionary selective pressures, it’s interesting to compare recognition of xenobiotics with the adaptive immune system. The latter, of course, exists to deal with a gamut of pathogens which otherwise would take over a host and replicate freely at the host’s expense. Internal surveillance against transformed cells (‘altered self’) to prevent tumor formation is another role for this advanced recognition system.

It is easy to conceive of ‘adaptive xenosensing’, where a novel (and poorly recognized) toxic environmental compound induces selective processes from populations of variant receptors on xenosensory cells, such that variants with greater affinity are selected and amplified. The power of this Darwinian process in action has been shown by the successful artificial generation of antibodies to ciguatoxin itself. This would not occur under natural circumstances, since it requires artificial conjugation of fragments of ciguatoxin to large protein carrier molecules, such that the toxin fragments act as immunological haptens. Nevertheless, this demonstrates that the adaptive immune system can indeed select for antibodies with the correct binding specificity against a toxic polyether molecule.

Why then does this not occur with xenosensing, to overcome poor initial responses to novel xenobiotics? (Here we return to this question as initially noted in the previous post). Once again, we must look to evolutionary explanations. Evidently the existing xenorecognition systems of vertebrates is selectively ‘good enough’ despite theoretical room for improvement, where the latter would require extensive investments in new developmental pathways with their consequent energetic demands. Above all, even the most poorly-metabolized compounds do not replicate, and (provided they are present in sublethal amounts) are gradually removed from organisms. Pathogenic and invasive organisms, on the other hand, will indeed replicate, and present an acute problem demanding adaptive solutions. And this is what evolution has bequeathed us: A xenorecognition system which is static in the lifetime of an individual, but variable through selective pressures over evolutionary time; and an immune system which is dynamically adaptive in time-frames much shorter than an individual life-span.

Bioorthogonality and Xenobiotics

We have considered ‘xeno-blindness’ as a hypothetical situation where a toxic compound elicited no response from an organism which had ingested it. (Such a molecule would ‘recognize’ one or more target molecules anywhere with the bounds of the host’s biosystem (and thereby manifest toxicity), but the foreign compound would fail to be recognized by any of the host’s xenodefenses, at any level). What if non-recognition is taken a step further still, such that the xenobiotic is neither toxic nor recognized? In such circumstances, we would be reminded of the notion of orthogonality, as raised in a previous post with respect to ‘weird life’. Our hypothetical compound which is completely ‘invisible’ (neither toxic nor xeno-recognized) would thus be considered bioorthogonal. Toxicity, of course, is the reason many compounds come to the attention of science in the first place. If the polyether metabolites of dinoflagellates were completely non-toxic, they would likely have escaped detection, given their low absolute amounts present in most marine samples. (Of course, they would still not be chemically ‘invisible’, and would eventually be picked up by modern sensitive metabolomic profiling – but this would be much delayed relative to the ‘flagging’ of their presence through their toxic actions).

A first thing to note in this regard is that bioorthogonality can be a relative concept. Consider that a compound could be ‘invisible’ in a specific cell type in culture, yet actively metabolized by cytochrome P450 enzymes expressed in liver cells in the whole organism from which the cultured cells were derived. In such circumstances, bioorthogonality might be assigned in the first case, but certainly not the latter. Yet even if bioorthogonality (or something approaching it) exists for an entire mammalian organism, this need not apply to the biosphere as a whole. Bacteria, after all, are the consummate masters of biochemical transformations, and can modify an astonishing range of compounds. Included among these are natural polyether toxins themselves, and a great many non-natural artificial compounds. A good case study of the latter phenomenon is the targeting of paraoxon (a toxic metabolite of the organophosphorus insecticide parathion) by the enzyme bacterial phosphotriesterase. This activity is believed to have evolved only within the last few decades, when paraoxon has become present in the environment, since no natural substrate for this enzyme is known.

It is thus not difficult to see that bioorthogonality can exist in discrete compartments (as in the case of a single cell type in culture noted above), but it is much more problematic to accept that any novel molecule would evade recognition within the entire biosphere. Such a hypothetical molecule could even be seen as a kind of orthogonal ‘dark matter’, but its existence would be very dubious for similar reasons to the possible existence of truly ‘orthogonal life’ on this planet intersecting with conventional life (as noted in a previous post). Certainly new artificial molecules released into the environment (such as DDT and other organochlorine compounds) persist for long periods, but again this is slow processing rather than total non-recognition, given that organisms capable of metabolizing such products are not evenly environmentally distributed. And, as exemplified by the above paraoxon example, bacteria can evolve efficient enzymatic recognition and processing extremely quickly, so any period of supposed ‘orthogonality’ would likely be short in any case.

It might be thought that any molecular entity even approaching the notion of bioorthogonality should exhibit chemical stability and low reactivity. At one level there would be seem to be some value in such a proposition, given the environmental and chemical stability of compounds such as fluorinated hydrocarbons (especially polymers thereof). But at another level, this cannot be correct. Certain heavily fluorinated compounds (including the simple molecule carbon tetrafluoride, CF4, but more commonly derivatives of methyl ethyl ether) have the property of acting as general anesthetics. And even the ultimate in non-reactivity, the inert gases, can induce such anesthesia. The inert (or ‘noble’) gas xenon has often been cited as a near-ideal anesthetic, with only its considerable expense limiting its much more widespread use. (It is a little ironic that the name ‘xenon’ has the same etymological route meaning ‘stranger’ as seen in all the ‘xeno-‘ words in this post). Xenon can in fact form a limited number of chemical compounds with highly reactive partners under specific circumstances, but there is no question of it forming any covalent bonds under physiological conditions.

Although there are vast numbers of artificial and naturally-derived drugs which bind non-covalently to their specific targets (and thereby act as inhibitors or other functional modulators), all of these are subject to some level of recognition by other proteins within the xenosensing system, followed by subsequent xenoprocessing involving covalent modification. This, of course, is the underlying basis of all drug metabolic studies. As we have seen, some xenobiotics are metabolized at a very slow rate. In this post, complex polyethers are the key exemplars, but dioxin (TCDD) is another important case in point, as discussed in the previous post. In neither case, however, can slowness of metabolism be in any way equated with complete invisibility to xenoprocessing mechanisms. Thus, while the mode of action of drugs may very often be via non-covalent interactions, drug processing (the xenorecognition system) involves at least a low level of covalent modification. As noted above, it could be argued in principle that very slow metabolic attack on highly resistant xenobiotics might proceed through the action of reactive oxygen species, whether deriving from cytochrome P450 activity (or other processing enzymes) or more non-specifically. If the latter, the authenticity of the ‘xenorecognition’ might be called into question, if bona fide ligand-receptor interactions (even at a high level of promiscuity) were not involved. Even if this should be the case, the reactive oxygen species nevertheless derive from host metabolism, and so even very slow attack on xenobiotics from this source still would result in a failure of true bioorthogonality.

But normal xenoprocessing (or any non-specific oxidation) cannot be relevant in any way to xenon, since xenon will never undergo any covalent reactions in vivo. And yet xenon surely is far from bioorthogonal, given its dramatic ability to modulate conscious experience in vertebrate organisms. These observations indicate that bioorthogonality on the part of any xenobiotic factors cannot be described simply by a complete lack of covalent reactivity at all biosystem levels. (Note we cannot refer to ‘compounds’ or ‘molecules’ when including monatomic inert gases such as xenon). So while hypothetical bioorthogonality would necessarily involve a lack of reactivity, it would have to be defined as functional reactivity of any kind, whether covalent or non-covalent, and at any physiological level.

There’s an important area relevant to bioorthogonality already alluded to in a previous post , which concerns artificial development of chemical reactants and reaction process which themselves are orthogonal to biological systems in which they take place. But to do justice to it, that will have to wait until a later post.

So, to conclude with one of the subthemes used here:

One should note that ‘xeno’ means stranger

And possibly, terrible danger

A harsh bitter taste

Is no form of waste

It serves as a guardian ranger

References & Details

(In order of citation, giving some key references where appropriate, but not an exhaustive coverage of the literature).

‘…..the observation that certain taste receptors….. are also expressed in specific gut cells…’   See a review by Rozengurt & Sternini 2007.   ‘……recent results have suggested that they may have a role in limiting the gut-mediated absorption of potentially toxic molecules….’    See Jeon et al. 2011.  /   ‘…..or airway smooth muscle cells….’     See Deshpande et al. 2010.

For over 80 years, it has been known that genetic differences in humans determine the taste response….’    The phenomenon of ‘taste-blindness’ to phenylthiourea (phenylthiocarbamide) was first reported in 1931; see a review by Drayna 2005.

‘…..the specific T2R receptor responsible for signaling PTC bitterness has been identified…’    For details of this receptor (TAS2R38), see Bufe et al. 2005.

‘……this persistence [of the non-taster PTC allele] has led to the proposal that it may have a selective benefit preserving it within the gene pool. ‘ See Kim & Drayna 2005.

‘……the loss of functional sweet taste receptors in domestic cats……’   /   ‘ Recently, this observation has been extended to a range of other ‘complete’ carnivores.  It is a well-understood evolutionary principle that unnecessary genetic function will tend to be lost..….it is possible that other factors which positively select for sweet taste loss also operate in these circumstances.’     See Jiang et al. 2012 for details on carnivore loss of sweet taste. In general, an often-noted example of abrogation of unnecessary gene function is loss of the ability to synthesize vitamin C (ascorbate) by primates, owing to their fruit diets containing plentiful supplies of the vitamin.

‘   the sweet taste receptor can be definitely be triggered by …….some intensely sweet natural proteins.’   Proteins triggering the sweet taste receptor bind to a different site to that used by low-molecular saccharide sweet substances.   See De Simone et al. 2006.

‘  Poisonings of dogs and young children have been attributed to its [ethylene glycol’s] sweetness, although hard evidence for this seems to be lacking…’    See studies in dogs by Marshall & Doty 1990; Doty et al. 2006. Whether or not at least some dogs are prompted to consume ethylene glycol through its taste, non-sweet tasting cats and other obligate carnivores would presumably be completely resistant to this effect. (Note that dogs, like bears, are not in fact ‘complete’ carnivores, and can subsist on other foods).

‘…..the original source identified as the marine eukaryotic single-celled protists known as dinoflagellates….’    For some basic background on dinoflagellates, and especially their unusual genomics, see Lin 2011; Wisecaver & Hackett 2011.

‘….ciguatoxin is tasteless….’ See Park 1994Lehane 2000. ‘Tastelessness’ here refers to the highest concentrations of polyether marine toxins found in contaminated fish, which are clearly sufficient to intoxicate a human or other mammal. Thus, even if artificially massive concentrations of ciguatoxin (far in excess to that encountered in contaminated natural sources) stimulated a taste receptor signal, such a response would be clearly far too insensitive to be useful as a primary anti-toxic avoidance screen. So tastelessness here is a functional definition, even if not necessarily absolute.

Another intriguing observation in this respect is that a commonly-reported symptom of ciguatera intoxication is distortion of taste perception (dysgeusia), such as experiencing a metallic taste in the mouth. Recent evidence suggest that this arises from ciguatoxin (and related polyethers) interfering with voltage-gated ion channels in taste receptor cells. These channels are associated with neurotransduction of taste receptor signals, but must be distinguished from the taste receptors themselves (which are members of the very large G Protein-Coupled Receptor family). See Ghiaroni et al. 2005; Ghiaroni et al. 2006.It thus seems ironic that polyether marine toxins fail to effectively activate taste receptors in the first place, yet perturb their function once intoxication has occurred.

‘…..ciguatera …….is neurotoxic, perturbing the activity of voltage-gated sodium and potassium channels….’  See a review by Wang & Wang 2003; and a more recent sudy by Pérez et al. 2011.

‘…..ciguatera toxicity in humans can persist ……consistent with slow metabolic turn-over…’ See Lehane 2000; Chan & Kwok 2001; Bottein et al. 2011. Note that (without further information) this is by no means proof of actual persistence of the original toxic molecule, given the formal possibility of ‘hit-and-run’ ongoing pathological effects, as noted for the neurotoxic chemical MPTP in a previous post.

‘….exposure of mice to ciguatoxin is associated with transcriptional activation of Phase I and II xenobiotic responses….’ See Morey et al. 2008.

A maritime fish-eating species in tropical areas which was regularly threatened by ciguatera poisoning would be under a strong selective pressure to evolve a better xenorecognition system….’    This specifically refers to land-dwelling or semi-aquatic animals rather than those which are fully marine. ‘Red tides’ of dinoflagellate blooms are often associated with massive fish kills, but in such cases it appears to be from release of toxins directly into local marine environments. Where this applies, improved xenorecognition could not promote avoidance. Even if protective mechanisms have evolved in an animal towards a toxin, massive transient exposures may still have lethal consequences.

‘….. possible that some tropical fish have the latter kind of protection [detoxifying or internally sequestering polyether toxins]….’   In this regard, it is interesting to note that a natural inhibitor of the toxic effects of at least one polyether marine product (bevetoxin) has been isolated, albeit in this case from dinoflagellates themselves. (Production of the inhibitor as well as the toxin in varying proportions by dinoflagellates may contribute to the variable magnitudes of fish kills during ‘red tides’). See Bourdelais et al. 2004.

‘….only a three amino acid residue difference in the human vs, insect sodium channel is the determinant of the differential toxicity of DDT….’    See O’Reilly et al. 2006.

‘…..successful artificial generation of antibodies to ciguatoxin….’    See Tsumoto et al. 2008; Ui et al. 2008.

‘ Why then does this [development of adaptive recognition systems] not occur with xenosensing, to overcome poor initial responses to novel xenobiotics….’    A similar scenario was raised in Searching for Molecular Solutions (Ch. 2, Molecular Sensing / Multirecognition. ) with respect to chemical sensing of odorants.

‘ Pathogenic and invasive organisms, on the other hand, will indeed replicate, and present an acute problem demanding adaptive solutions. ‘    A seeming paradox in this regard is the lack of adaptive immune systems in invertebrates, which are certainly just as prone to microbial assaults. One answer may lie in their possession of highly diverse innate immune receptors, and this is a topic for a later post.

Bacteria, after all, are the consummate masters of biochemical transformations …..Included among these are polyether toxins……’ See Shetty et al. 2010.

‘…..phosphotriesterase. This activity is believed to have evolved only within the last few decades….’    See Raushel & Holden 2000; Aharoni et al. 2005.

‘…..certain heavily fluorinated compounds …… have the property of acting as anesthetics….’    See Smith et al. 1981; Koblin et al. 1999.

‘…..the inert gases, can induce such anesthesia…..’    Xenon, krypton, and argon have anesthetic properties, but xenon is the most useful in having such effects under normal conditions of pressure. See Kennedy et al. 1992. Although the mechanism of inert gas anesthesia is uncertain (as are mechanisms of anesthesia in general), xenon has long been known to be capable of binding to hydrophobic pockets in proteins (See Prangé et al. 1998), which might be associated in some way with its anesthetic activity.

Xenon can in fact form a limited number of chemical compounds with highly reactive partners under specific circumstances….’    The first xenon compound (xenon hexafluoroplatinate; also the first compound of any of the noble gases) was prepared by Neil Bartlett in 1962. For a review of this and progress in inert gas chemistry in general, See R. B. Gerber’s very useful article from the Israeli Chemical Society site.

Next post: July.

2 Comments leave one →
  1. emily permalink
    January 20, 2016 9:29 am

    what are the sources for your figures? I would like to use them for an informal presentation, but feel i need a more credible/obvious
    source. would you be able to inform me of the article/source you derived them from? thanks! (also very informative!)

    • February 21, 2016 9:34 pm

      Hi Emilu,

      In general, the sources are from the papers I cite, but often they reflect my own synthesis of a wide range of available knowledge. If you are specially referring to the figure from Xenobiotic Recognition Repertoires, see Tsumoto et al. 2008 as linked in that post. ( Tsumoto et al. JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 283, NO. 18, pp. 12259–12266, May 2, 2008). Hope that is helpful – I’m sorry to be so slow in responding.

      Best regards, Ian

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s