PRINCIPLES OF TOXICOLOGY - Biology East Borneo

3.2 BIOTRANSFORMATION REACTIONS 79Not all inhibitors relate to enzymes located in membranes. There are inhibitors of nonmicrosomalxenobiotic-metabolizing enzyme activities that have toxicological importance and clinical usefulness.Disulfiram, an inhibitor of aldehyde dehydrogenase, is used as an adjunct to behavioral modificationin the treatment of alcoholism since the unpleasant symptoms elicited by the accumulating acetaldehydeare sufficient to dissuade further ethanol ingestion. Monoamine oxidase inhibitors are availableas drugs for the treatment of depression. If chemicals (e.g., tyramine) normally adequately metabolizedby these enzymes are ingested simultaneously, they may accumulate to a sufficient concentration tocause severe toxicity (hypertensive crisis). Esterases where the active center contains a serine residueare readily inhibited by organophosphates and carbamates. Such inhibition results in the accumulationof other chemicals undergoing hydrolysis, particularly the endogenous substrate, acetylcholine, to thepoint of toxicity.Other Factors Responsible for Variations in Xenobiotic Metabolizing EnzymesAnimal Species and Strain Much has been made of species differences in xenobiotic metabolism,both for the purposes of extrapolation to humans and for exploiting differences in the understandingof species selective toxicities. Rodents have higher cytochrome P450 concentrations than othermammalian species, birds, and fish. Among mammals, cats are particularly deficient in UDP-glucuronosyltransferaseactivities and fish are deficient in all conjugations. This latter point has beenattributed to the lesser need of aquatic animals to render foreign compounds to their most water-solubleform, since the volume of water that xenobiotics can diffuse into via the gills compensates for the lowerpartition coefficient. In comparison to most laboratory animal species, the rat is well endowed withsulfotransferase activity, a little lower in cytochrome P450 concentration, and relatively deficient inglutathione transferase activity (Table 3.8).TABLE 3.8 Species and Strain Variations in Xenobiotic-Metabolizing Enzymes aPhase IPhase IISpecies and StrainP450pNAdeMUGTGT1 GT2 GST ST(vs. Male Sprague–Dawley Rat)Rabbit b 140 — 250 275 575 140Hamster 160 300 155 235 470 25Rat: Fischer 90 125 115 115 55 —Rat: Gunn 125 — 30 120 — —Mouse: D2 85 245 60 170 225 320Mouse: B6 — 85 325 90 325 235Mouse: CF-1 120 490 — — 265 —Mouse: SW b 105 — 65 220 200 50Guinea pig b 105 — 180 95 415 30Cat b 60 — 5 50 75 50Dog b 70 — 335 355 85 30Quail b 45 — 220 25 75 35Trout b 68 — 5 20 60 10a Abbreviations: pNA deM—p-nitroanisole demethylase; UGT = UDP-glucuronosyltransferase (two isozymes: GT1 and GT2);GST = glutathione S-transferase; ST = sulfotransferase; SW = Swiss Webster.b Gregus Z, Watkins JB, Thompson TN, Harvey MJ, Rozman K, Klaassen CD, Toxicol. Appl. Pharmacol. 67: 430 (1983).