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Another Level of Xenoprotection

July 30, 2012

The recent series of posts have featured different levels of recognition of environmental poisons and related defense processes, ranging from taste receptors to drug export mechanisms. But one layer has not been addressed so far, and this is the present theme.

 Evicting Poisons

 This oversight on my part was drawn to my attention by no less than a domestic cat, not normally known for paying much attention to blogs of any description. In my presence, this little animal suddenly vomited up half a cigarette, an improbable addition to what most observers would consider a healthy feline diet. Forgive my bringing this up, so to speak, but it did serve as the springboard for further thoughts. It’s not clear what the consequences of ingesting cigarettes would be for cats, but presumably it would not have much nutritional benefit. But whatever prompted eating this suspect item in the first place (which we’ll consider a little further towards the end of this post), the cat’s stomach (or at least some part of its digestive apparatus) strongly and emphatically pressed a metaphorical reject button, and saved this pet from perhaps an unpleasant nicotine-related encounter. (Rest assured, she was none the worse for the experience, and didn’t have to clean up the mess).

In previous posts (28th March and 30th May of 2012), the bitter taste receptors were considered as a frontline defense against ingestion of environmental poisons. Anything getting past this guard level then can potentially be neutralized through a variety of xenorecognition and xenoprocessing mechanisms (also considered in a previous post).  Indeed, but in between lies another level of defense, as any cigarette-eating cat could show you. Bad things that get past the oral cavity into the stomach can potentially be prevented from proceeding to do harm to the whole organism, if they can be physically ejected as soon as possible. Regurgitation can at least greatly reduce a toxic load, potentially bringing down the exposure to levels manageable by other xenoprocessing mechanisms, and thereby having life-saving (and in turn, evolutionary fitness) implications. This area might seem trivial, but further thought shows that it certainly is not. Regurgitation is a complex and coordinated series of muscular actions, which clearly must have some kind of trigger to initiate. What external agents then stimulate this response, how are they recognized, and how is the resulting reflex produced?

Emetogens and Their Receptors

 A particular focus of attention in the field of emesis has arisen as a result of empirical results in cancer chemotherapy over decades of its application and continuous refinement. Put simply, in the absence of simultaneous anti-emetic treatments, some anticancer drugs are highly emetogenic (inducing nausea and vomiting), but there are marked differences in their relative potencies in this regard.  For example, the well-known drug cisplatin, a tremendous advance in the treatment of certain tumors, is nonetheless notorious for its emetogenic effects. On the other hand, drugs such as vincristine and bleomycin are very low in inducing this highly unpleasant side-effect, although they certainly must be administered with great care due to their toxicities. (Conventional anticancer drug cytotoxicity typically has low selectivity towards tumors, and thus any dividing host cell may be potentially affected as ‘collateral damage’).

Much clinical research has understandably focused on ways for minimizing the distressing induction of emesis by the necessary anticancer regimens. Effective anti-emetic drugs target relevant neural receptors (such as the 5-hydroxytryptamine(serotonin)3 receptor) involved in transmission of the emetogenic signals. As one would expect for a complex behavior pattern, emesis is ultimately controlled by the brain. In terms of the complexity of emetic effects, it should be noted that in addition to specific substances, vomiting can be induced by pregnancy or physical stimuli (as with motion sickness) or arise from psychogenic origins (consider any distressing influence which is literally sickening). At one time, a specific neural center was postulated to act as an emetic controller, but more recent evidence suggests cooperating regions of the medulla oblongata (in the hindbrain) are involved. Input signaling implicates a region of the medulla called the Area Postrema, which very significantly is not restricted by the blood-brain barrier, and thereby able to potentially sample blood-borne xenobiotics. In addition, other evidence suggests emetogenic primary signaling originates from intestinal sites. Gut vs. blood-borne sensing might be viewed as two separate levels of emetogenic detection, since orally ingested poisons will normally encounter the gut receptors first. Nevertheless, in both cases the chemosensing and neural transduction of signals have common results.

Yet this information does not directly address the nature of the chemoreception which transduces toxin-induced emetic signaling in the first place, and it is apparent that there is still much to be learned in this area. It would seem reasonable to postulate a role for bitter taste reeeptors in this signaling process, based on the assumption that specific chemoreceptors are involved. This follows from relatively recent observations showing that the TAS2R bitter receptors are not only expressed in taste buds, but at a number of distinct anatomical sites, including the gut and the brain. (This was also alluded to in the previous post). More indirectly, the redeployment of a primary xenoreceptor set in a second-round protection mechanism would from first principles appear to be a parsimonious evolutionary pathway.

Still, no evidence appears to support this proposal at present. But if TAS2R receptors were involved, it might be predicted that at least a broad correlation would exist between the perception of bitterness and emetogenicity of a compound. (In other words, this would propose that the more bitter a compound, the more it would tend to induce emetic effects). But this proposition can immediately be challenged on several grounds. Firstly, emesis can be induced by sufficient concentrations of simple salts (such as lithium chloride or copper salts), which do not engage bitter taste reception. And secondly, no evidence suggests any significant correlation between the degree of bitterness and emetogenicity of a compound, although systematic information in this regard seems to be lacking. One problem in this regard is measurement of emetogenic potential itself, and its variation between species. (Obviously, human experimentation in this area can have many ethical constraints). But the absence of discernable linkage between bitterness and emetic potency is conveyed through the bitterest known compound, ‘denatonium’, an artificial derivative of the anesthetic lidocaine. Despite this compound’s intense bitterness, it has low toxicity relative to many natural bitter substances (noted further below). While denatonium salts are likely to induce emesis if the dose is high enough, this question does not appear to have been systematically studied. But at least, if the emetogenic signal paralleled the bitter perception, denatonium would also be the most potent emetogen, and there is certainly no evidence for this. For another piece of relevant information, the low emetogenicity of the anticancer drug vincristine (noted above) is notable with respect to its nature as a bitter-tasting plant alkaloid. Therefore, bitterness per se and emesis cannot be closely associated.

Nevertheless, these observations do not rule out a role for bitter taste receptors in emesis, since many complicating factors might cause divergence between the perceptual signaling of bitterness, and signaling from the same receptors in different physiological sites. For example, both the range of specific TAS2R receptors and their signaling transduction mechanisms might differ between oral and gastric or brain receptors, such that a strong bitter signal does not necessarily produce an analogously strong emetic response. Additional taste receptors beyond the TAS2R set might also be involved, as a possible explanation for emesis induced by salts (also noted above).  Thus, as in a great many areas of biology, only a positive read-out here is very useful. (In other words, if a very strong correlation between perceptual bitterness and emetogenicity did exist, it would certainly be consistent with the use of TAS2R receptors in both contexts – but even this, of course, would require more direct information before being proven).

Emetic Signaling

In a general model of signaling which leads to emesis, cells receptive to chemical or other stimuli secrete neurotransmitters upon activation, which in turn activates adjacent neural signaling cells, with resulting common higher-level sensation and behavioral outcomes (nausea and vomiting). By such means, similar effects can be elicited by diverse signals, ranging from a variety of chemicals (from inorganic salts to complex organic compounds), to disagreeable motion stimuli and psychogenic causes. This arrangement has a certain logic to it, since it is unnecessary for the final results (emesis) to qualitatively differ as a consequence of different origins. In this sense, the emetic signaling may be considered convergent from different receptors and different neurotransmitters towards a common neural response. This can be contrasted with the sense of taste, which has both divergent and convergent aspects. With respect to the latter, a wide range of different compounds activate TAS2R bitter receptors, and different sets of compounds (albeit probably less diverse) also converge on activation of sweet receptors. But since the biological functions of bitter and sweet sensing are radically distinct, it would make no sense for their sensory output to converge, and this is obvious from experience. (It is also consistent with recent studies showing divergent brain regions activated by the respective types of taste stimuli).

Since antagonists of relevant neuroreceptors (signal blockers) are effective anti-emetics, it might be expected that corresponding agonists (signal activators) should be strong emetic agents. Such agents would then directly potentiate the signaling neural cells, rather than indirectly via chemoreception (for example) and specific neurotransmitter release. While not false, such reasoning is nonetheless simplistic, since specific neurotransmitters typically bind not just one but a family of receptors, each of which can transduce distinct signaling outcomes. The activity of an agent then is greatly dependent on its specificity for a particular receptor subtype, and the nature of its interaction. Yet there are certainly precedents. As noted above, many anti-emetic drugs target the 5-hydroxytryptamine3 receptor, and an agonist of this same receptor, phenybiguanide, is (among other pharmacological properties) a strong emetogen. Neurotransmission triggered by the peptide mediator cholecystokinin also is involved in emesis, and a particular cholecystokinin variant (CCK-8) is a highly potent emetic in humans, far more so even than the most active cancer cytotoxic drugs.

In this brief overview, the possible role of taste receptors in emesis has been considered, but olfactory receptors might also be implicated in humans. In this case, associated serotonin release again provides a mechanistic convergence with above-noted emetic signaling processes. Certainly some chemicals can invoke a nauseous response simply from exposure to their volatile odors (pyridine is one example that comes to mind, from personal experience).

Non-emetic Mammals and Behavior-driven Xenoprotection

While considering the role of emesis as another level of xenoprotection, one must account for circumstances where it is absent. This is well-demonstrated by rats and mice, whose physiology does not permit the emetic reflex. It has been suggested that these rodents side-step the need for vomiting to some extent through highly sensitive food sampling behavior, and conditioned avoidance of foods which have undesirable effects. Failing this, such animals have been shown to ingest inorganic materials (especially clays), which act as adsorptive detoxifying agents, a behavior termed pica. The interesting parallel between pica and emesis is shown by experiments where rat pica is induced by emetogens and mitigated by anti-emetic drugs. Given these observations, both learned food avoidance and pica emerge as xenoprotective strategies, where higher-level behavior patterns are crucial elements. Conditioned food avoidance in rats has been associated with chemosensing in the Area Postrema, noted above as an important signaling center in emetic animals. Pica has certain conceptual overlap with ‘zoopharmacognosy’ (considered in detail in a previous post, where animals ‘self-medicate’ by consuming environmental bioproducts (principally plant materials) for health-related reasons. Such innate behavior patterns have clear survival value, and would be positively selected on that basis.

Given the proposed increased reliance of rats on primary taste sensing for detecting (and subsequently avoiding) noxious substances, it is of interest to note apparent strong divergences between rat and human bitter taste perception. In particular, the above-mentioned denatonium, exquisitely potent as a bitterant as measured by human sensing, is markedly less so in rats. This is clearly evident through a practical use of denatonium salts as safety additives to rat poisons, in order to help prevent accidental consumption by humans (especially children, whose aversion towards bitterants tends to be stronger than adults). Obviously, this strategy would fail if rats were as sensitive towards the intense bitterness of denatonium as are we humans ourselves. From a rat’s point of view, this might seem unfortunate, but in reality, at least in this specific instance the rat bitter taste responses are much more in tune with the actual toxicity of denatonium. (The human perception of denatonium is far out of proportion to its toxicity, as noted a little further below). It would be interesting to see if the bitter taste perceptual repertoire of rats in general has a better correspondence with actual chemical toxicity than that shown by human responses. This too would be in line with more intense selection pressures on rat bitterant tasting than for primates during the evolutionary past.

In humans, bitterness vs. toxicity can be addressed by comparing thresholds of bitter taste with toxic responses for a wide range of compounds. Assessing the outer limits of bitterness can usually be done (with highly dilute solutions of test compounds), but lethal dosages can only be obtained through accidental poisonings, which obviously are both undesirable and poorly controlled. The situation is almost the opposite with rats, where controlled toxicity testing is a standard laboratory practice, but rats generally have trouble reporting when they first can perceive bitterness in a dilution series of a compound. In lieu of this, minimal chemical concentrations creating aversion can be tested, but this is not the same thing as assaying the lowest concentrations perceivable. More sophisticated testing is possible with in vitro assays for triggering of human vs. rat taste receptors, but this is at the level of primary signaling rather than perceptual awareness. An example of some assembled literature data is shown below, incomplete for the rat, but which partially illustrates the disconnect between human perception and toxic response for denatonium.

Top graph: Human bitterness indices for denatonium, strychnine, and brucine, equivalent to bitterness thresholds for each, normalized to that for quinine (i.e., where quinine bitterness index =1), compared to available information on approximate lethal adult dosages. (Note log scale on X-axis). These are compared with rat laboratory toxicity indices (LD50 values also normalized to that for quinine). The table below shows the original figures for calculating the indices. Note apparent differential susceptibilities for brucine vs. strychnine for humans and rats.

Sources: General: NCBI toxnet; Taste Perception in Humans, from Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001; The Alkaloids: Chemistry and Physiology, Volume 43. Geoffrey A. Cordell, Richard Helmuth Fred Manske Eds; Academic Press 1993. Also Hansen et al. 1993 (denatonium benzoate). Where appropriate, values shown here have been taken as the midpoints of measured experimental ranges.


In any case, with the inclusion of both conditioned aversion and the pica ‘toxic sequestration’ strategies, we can now define a broader picture of xenoprotection, as depicted below:

Schematic depiction of different levels of xenodefenses. A: Avoidance of noxious materials via aversive taste responses, which includes conditioned avoidance as observed with rats; B: Ejection of poisons via emesis, whether emetic sensing occurs within the gut or via sensing of blood-borne compounds; C: Sequestration of ingested poisons by ingestion of clays or related materials (pica); D: Internal xeno-defenses, as considered previously. For detail, see relevant previously-posted diagram, from the post of 28th March, 2012.


The paradox of bitterness

So far we’ve seen that, in humans at least, bitterness correlates poorly with the potency of chemical emetogenicity. But if we consider the perception of bitterness in its entirety, it becomes clear that it is an imperfect correlate with aversion itself, which is its accepted direct evolutionary rationale. It has been thus noted that complete avoidance of absolutely all bitter substances would have negative nutritional consequences. But if certain environmental compounds are potentially useful, why should these register as bitter in the first place? After all, bitterness is a perception resulting from triggering of specific receptors, not an inherent property of a molecule, so for what reason should a useful molecule be thrown into the same ‘bitter’ grab-bag as for a motley collection of poisons?

One issue in at least a subset of cases could be the existence of similarities in molecular shape between potentially useful compounds and wholly deleterious poisons, such that they are recognized by the same range of TAS2R bitter receptors. While evolution of receptors capable of discriminating even subtle molecular differences is possible in principle, such changes may be constrained in practice by lack of effective selective pressures. But in any case, a better evolutionary result (as dictated by fitness benefits) might simply be more nuanced perception related to the strength of the bitterness signal. A low-level bitter taste (especially when other tastants are also present) might overlap with a pleasure response in some circumstances. So a weakly bitter (but possibly useful) nutrient might then be consciously ingested, but the background bitterness would serve to limit overdosing. Certainly in human adults, a certain amount of bitterness in food or drink is often prized. Among many possible examples, the alkaloid quinine (long employed as a treatment for malaria, as noted in a previous post) is still used as a bitterant in certain drinks, including bitter lemon or tonic water. Given that the preference for this kind of additive is not everyone’s ‘cup of tea’, the variation therein probably arises from a combination of both genetic differences in taste receptor repertoires and positive conditioning towards acceptance (development of an ‘acquired taste’). But there are levels of bitterness beyond which no normal human will voluntarily go. It was for that reason that reference to bitterness as an aversive factor in previous posts often included the adjective ‘intensely’, to distinguish such uniformly negative perceptions from lower-grade bitterness which in some people provides a pleasurable stimulus.

Finally, the ‘bitterness paradox’ prompts a loop-back to the cat and the cigarette which initiated this post. Despite the bitterness and potential aversive power of tobacco, it remains a possibility that it was consumed from an instinctive drive towards ingesting potentially anti-parasitic compounds. If so, it might be case of innate feline zoopharmagnosy. Indeed, there is evidence that leaves of the tobacco plant have certain antiparasitic properties, and cats regularly consume grasses if given the opportunity, which might in part be related to innate ‘self-medication’. Even so, the negatives of cigarette-eating probably outweigh any potential benefit, and such behavior could then be considered a misfiring of an instinctive programming mechanism.

Anyway, to conclude with a biopoly(verse) offering on the poison sequestration theme:

 Rats can never show emetic display

So what control keeps rat poisons at bay?

Through a sudden ‘Eureka!’

Comes the answer: It’s pica!

They thus sequester their toxins with clay.

This one hinges on what is apparently a non-standard pronunciation of pica as ‘peeker’. Although some sources do give this as a possible alternative, more usually it is rendered as sounding like ‘piker’. While this is not an Earth-shattering issue for most purposes (‘you say tom-may-to, I say tom-mah-to…’) it does tend to ruin a little verse if one’s pronunciation expectations are violated. So, to accommodate the alternative:

When poisoned, a rat may eat clay

(Emesis is never the way)

Perhaps this is like a

Sick human with pica

In keeping bad toxins at bay.

References & Details

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

‘……this little animal suddenly vomited up half a cigarette…..’    This cat had access (now curtailed) during daylight hours to a frontyard and sidewalk where (regrettably) passers-by sometimes leave cigarette butts, and apparently inadvertently drop whole cigarettes on occasion.

‘…..the well-known drug cisplatin… nonetheless notorious for its emetogenic effects…..’    This is graphically described in Siddhartha Mukerjee’s prize-winning cancer book The Emperor of All Maladies (Fourth Estate, 2011) in which it was noted that nursing staff in oncology units nicknamed cisplatin ‘cis-flatten’.

‘…..drugs such as vincristine and bleomycin are very low in inducing this highly unpleasant side-effect [emesis].’    For a review including the of classification of cancer cytotoxic drugs by their emetogenic potential, see Hesketh 2008.

‘….target relevant neural receptors ….’     See again Hesketh 2008, and also Navari 2009.

‘…..more recent evidence suggests cooperating regions of the medulla…..’     See Hornby 2001.

‘…..the Area Postrema…..’     This has also been referred to as the ‘chemoreceptor trigger zone’. See Miller & Leslie 1994; Shinpo et al. 2012.

‘……emetogenic primary signaling originates from intestinal sites.’    See again Hesketh 2008; and Andrews & Horn 2006.

‘……TAS2R bitter receptors are not only expressed in taste buds, but at a number of distinct anatomical sites, including the gut and the brain.’    For a recent general perspective on non-perceptual roles of taste receptors, see Trivedi 2012. For a specific view of TAS2Rs in gut sites, see Rozengurt & Sternini 2007; for brain, see Singh et al. 2011.

‘….the most parsimonious pathway to take.’    The notion of biological modularity is encompassed within an interesting paper of Weiss 2005.

‘…..emesis can be induced by sufficient concentrations of simple salts…..’    These include lithium chloride and copper sulfate; see Percie du Sert et al. 2012.

‘……measurement of emetogenic potential itself, and its variation between species.’    An extensive review of the literature on emetic induction with a variety of agents across a range of species was conducted and analyzed by Percie du Sert et al. 2012. Apart from measurement inconsistencies between species, animal assays for emesis can be distressing, so alternatives are being developed. See Robery et al. 2011 for work in this regard with the none-sentient social ameba Dictyostelium.

‘…..denatonium….’     This name comes from its use in rendering alcohol undrinkable, or ‘denatured’. It has widespread application as an aversant added to moderately toxic materials to discourage consumption, especially from children. As a quaternary substituted nitrogen compound, it is usually produced as benzoate or saccharide salts. See Hansen et al. 1993.

‘…..recent studies showing distinct brain regions activated by the respective types of taste stimuli…..’     See Chen et al. 2011.

‘…..phenybiguanide …… an emetogen….’    See Miller et al. 1994.

‘……cholecystokinin variant (CCK-8) is a highly potent emetic in humans….’    Cholecystokinin occurs a 33-mer peptide, but also as shorter truncated forms which retain activity, including the octamer CCK-8. For detail on the emetic properties of CCK-8 in comparison with other agents, see Percie du  Sert et al. 2012.

‘……olfactory receptors might also be implicated in humans…..’    See Braun et al. 2007.

‘… rats and mice, whose physiology does not permit the emetic reflex….’    For an excellent (and fully referenced) account of this and many related areas (such as pica), see Anne Hanson’s rat behavior site, which also includes a list of known emetic behavior in a wide range of vertebrates.

Conditioned food avoidance in rats…..’     This rat behavior has alternatively been referred to as ‘delayed learning’; also discussed in a previous post concerned with zoopharmacognosy.

‘….a behavior termed pica.’    The extent of pica in rats has been shown to correlate with the degree of emetogenicity of anticancer drugs in humans (Yamamoto et al. 2007).  De Jonghe et al. 2009 have also provided evidence that consumption of kaolin (a type of clay) by rats can assist recovery from doses of the anticancer cytotoxic drug cisplatin. Pica has been documented also in emetic animals, and certainly humans are included in this regard. While human consumption of clays or related materials is mostly an abnormal behavior, in certain circumstances it has been proposed to have positive effects associated with correction of micronutrient deficiencies. The increased incidence of pica in pregnant women has been long noted, and this is possibly associated with benefits from protection against toxins. (See Young 2010). It is interesting to compare this with apparent zoopharmacognosy in pregnant lemurs through the consumption of tannin-rich plant materials (noted in a previous post).

Conditioned food avoidance in rats has been associated with the chemosensing in the Area Postrema……’     See Ossenkopp & Eckel 1995; Eckel & Ossenkopp 1996.

‘…..denatonium, exquisitely potent as a bitterant as measured by human sensing, is markedly less so in rats….’     Some results seem to indicate that denatonium salts may be no more bitter to rats than is quinine. See Kaukeinen & Buckle 1992.

‘…..complete avoidance of absolutely all bitter substances would have negative nutritional consequences.’    See commentary of Calloway 2012.

‘……genetic differences in taste receptor repertoires……’     For more on genetic differences in human taste perception, see the previous post. Evidence for positive selection during human evolution of certain bitter taste receptor alleles has been demonstrated; see Soranzo et al. 2005; Li et al. 2011.

‘…..there is evidence that leaves of the tobacco plant have certain antiparasitic properties.’    See Iqbal et al. 2006.

Next Post: September.

2 Comments leave one →
  1. Marc Larence permalink
    November 13, 2012 4:13 am

    Day to day i always feel nausea and it is mostly caused by my astigmatism (eye problems). There are other causes of nausea and mostly they are benign.:

    Brand new posting on our very own blog site

    • December 4, 2012 5:50 am

      Certainly nausea can be induced by factors beyond the ingestion of noxious chemical agents; I noted in this post that psychogenic or physical stimuli (such as motion sickness) could also have such effects. I presume certain eye problems and their resulting effects would fall into the latter category. But whatever the mechanisms for such non-chemically induced nausea, it remains the case that emesis can function as another level of protection after a dangerous substance has been ingested. (At least for humans, and not non-emetic mammals such as rats).

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