PRINCIPLES OF TOXICOLOGY - Biology East Borneo

3.3 SUMMARY 85been shown to be responsible for the production of glucuronides, which, via protein alkylation, canresult in the formation of immunogens. The immune response mounted to these aberrant moleculescan be highly toxic to organisms. Examples of toxic conjugates (acyl-linked glucuronides andglutathione adducts) are shown in Figure 3.13 and Table 3.11. Glutathione conjugates can also serveas transport forms of reactive intermediates. Methyl isocyanate, a highly reactive electrophile, is suchan example. The glutathione conjugate is transported to sites distant from the initial absorption site tocause toxicity to other organs.The balance between detoxication and bioactivation of xenobiotics by metabolism enzymes can bedramatically changed by the induction or inhibition of the enzymes. Enzymes that are normally presentat low levels, and therefore do not bioactivate toxicants to reactive intermediates, can become activeparticipants in the toxicity of chemicals when the levels and activities of the enzymes are increased.Many examples of this situation exist. For example, induction of CYP2E1 by ethanol results in thegreater bioactivation of hepatotoxins like CCl 4and acetaminophen or carcinogens such as dimethylnitrosamine.Although the toxicants can produce damage normally, their potency is greatly increasedafter induction of CYP2E1; specifically, toxicity is elicited at much lower doses because more of thechemical is oxidized to a reactive intermediate.Conversely, the toxicity of many chemicals can be ameliorated by induction of enzymes that areresponsible for the detoxication of the compound. Bilirubin can cause significant central nervoussystem damage in neonates where the UDP-glucuronosyltransferase(s) that detoxify this naturallyoccurring heme breakdown product are present in low amounts. Inducing the levels of the necessaryUDP-glucuronosyltransferase by drugs such as phenobarbital increases the glucuronidation of bilirubinand decrease its toxicity. In the same way that induction of bioactivation enzymes can increasetoxicity and induction of detoxification enzymes can decrease toxicity, the inhibition of bioactivationenzymes or the inhibition of detoxification enzymes should decrease or increase toxicity, respectively.The carcinogenicity of complex mixtures of polycyclic aromatic hydrocarbons is sometimes found tobe less than one would expect if the relative carcinogenicity of each component were summed. Aprobable reason for this decrease in toxicity lies in the inhibition, by components of the mixture, ofthe cytochrome P450 enzymes that bioactivate the carcinogens to their DNA-reactive intermediates.The mechanisms by which xenobiotics cause toxicity can be highly diverse, and elucidating theprecise biochemical and chemical mechanisms that induce toxicity can be a difficult process. Thereare many tools available that can be used to evaluate toxic mechanisms. They include the use of animalspecies, gender, or cellular differences that vary widely in their response to the toxin. For example,naphthalene is highly toxic to mice when administered by the intraperitoneal route or by inhalationbut is much less toxic to rats. Investigators have used this species differences to provide vitalinformation about a cytochrome P450 (CYP2F2) that is highly expressed only in murine lung and isresponsible for the bioactivation of this toxicant. Limonene causes severe renal toxicity to male ratsbut not female rats. The primary cause for the toxicity was eventually linked to the expression of aglobulin that is not expressed to a significant degree in female rats. An example of the use of specificcellular targets is with the nephrotoxic glutathione conjugates of halogenated hydrocarbons, such ashexachlorobutadiene, which are selective for the proximal tubule cells of the nephron. Analysis showedthat these cells contain high amounts of the enzyme C-S lyase, and it is this enzyme which is responsiblefor the production of the electrophilic intermediates from these toxicants. Similarly, it is the highcontent of monoamine oxidase B in dopamine-containing neurons linked with the cellular selectivityof the toxicity of MPTP that has enabled the mechanism of bioactivation of this toxicant to beelucidated.3.3 SUMMARYBy altering a portion of a chemical or by adding another molecule to it, drug-metabolizing enzymescan alter the toxicity of the chemical, its tissue-binding properties, and its distribution and durationwithin the body.