PRINCIPLES OF TOXICOLOGY - Biology East Borneo

76 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATIONwith a transporter protein (ARNT) in the nucleus, it initiates the transcription of mRNA to a limitednumber of proteins, including certain isozymes of cytochrome P450 (e.g., CYP1A isozymes) and UDPglucuronosyltransferase(GT1), by binding to a regulatory region of these genes. The region of DNAto which it binds has been termed a xenobiotic response element (XRE). These mRNA molecules moveout of the nucleus and are translated into new proteins on the ribosomes attached to the endoplasmicreticulum. The burst of mRNA production is usually seen within hours of exposure to the inducingagent. For increased amounts of active cytochrome P450, a coordinate induction of additional hemein the mitochondrion is also needed. Much of the information on this induction mechanism arose fromwork with the “nonresponsive” strains of mice (e.g., D2, CF-1; see Table 3.6) in which the Ah receptorappears defective with respect to its affinity for the polycyclic aromatic hydrocarbon. No suchwell-defined deficiency has yet been found in rat strains or humans.The list of compounds that induce drug-metabolizing enzymes in a manner different from that ofpolycyclic hydrocarbons is much more extensive and includes chemicals of diverse chemical structureand biological effect. For some of these groups of chemicals (e.g., phenobarbital), no receptor has sofar been identified. Different isozymes of the chemical/drug-metabolizing enzymes are induced (seeTables 3.4 and 3.6), and in contrast to the polycyclic hydrocarbons, many cause a marked proliferationof the endoplasmic reticulum and increase in liver size. Some of the induction seen with many of theseagents has been attributed to a stabilization of existing enzyme in addition to the formation of newenzyme either via enhanced mRNA production (transcription) or changes in the translation rate ofbasal amounts of mRNA.Nonmicrosomal enzymes, including sulfotransferases, are not induced as extensively as aremicrosomal enzymes. Exceptions are the cytosolic GSH transferases, which are induced by a widerange of agents (see Table 3.6). Extrahepatic microsomal enzymes are induced by a more restrictednumber of compounds compared to those that are able to induce liver enzymes, and polycyclic aromatichydrocarbon-type induction predominates.A similar degree of induction of both phase I and phase II enzymes does not always occur and canresult in an imbalance in the ability of phase II reactions to conjugate all the reactive centers generatedby the enhanced phase I activity (e.g., dexamethasone and pregnenolone 16α carbonitrile; Table 3.6).Sometimes, Phase II enzyme activities are increased with little (e.g., tioconazole, isosafrole; Table 3.6)or no (e.g., 2,2′-dipyridyl, 3,4-benzoquinoline; Table 3.6) effect on phase I enzymes. Changes inUDP-glucuronosyltransferases may be preferential for one or the other major isozyme (e.g., GT1 >GT2 for 5,6-naphthoflavone, 3-methylcholanthrene, and 2,3,6,7- tetrachlorodibenzodioxin; GT2 >GT1 for troleandomycin, phenobarbital, clotrimazole, and isosafrole). Changes in microsomal UDPglucuronosyltransferaseenzymes may (e.g., clotrimazole, isosafrole, and β-naphthoflavone) or maynot (e.g., fluconazole) be accompanied by major induction of the cytosolic glutathione S-transferaseactivity.The consequences of induction can be diverse. An inducing substance may increase the metabolismof one or more other xenobiotics and can even increase its own metabolism. Induction of microsomalenzymes can also enhance the metabolism of endogenous substrates such as steroids and bilirubin.Thus, induction may be important to consider in multiple drug therapy, chronic toxicity tests, crossoverdrug testing, and environmental toxicology. Some drug tolerance is explained by increased inactivationof the drug by induced enzymes. When major increases in phase I enzymes producing reactiveintermediates are not matched by similar increases in the phase II enzymes responsible for theirsequestration, increased toxicity may result.Induction is qualitatively, if not quantitatively, similar in most common laboratory animal species,although the rat is perhaps the most responsive (see Table 3.7). Induction is known to occur in humans,often necessitating a change in the therapeutic dosage regimen of drugs. However, for some agents(e.g., peroxisome proliferators), the inductive response seen in experimental animals is absent inhumans at therapeutic doses.Although small differences are evident, the effects of inducers are also similar between strains ofa species and between species. Thus, information derived from studies in one laboratory animal speciescan generally be assumed to occur in another. From the examples given in Table 3.7, the phenobarbi-