PRINCIPLES OF TOXICOLOGY

3.2 BIOTRANSFORMATION REACTIONS 79
Not all inhibitors relate to enzymes located in membranes. There are inhibitors of nonmicrosomal
xenobiotic-metabolizing enzyme activities that have toxicological importance and clinical usefulness.
Disulfiram, an inhibitor of aldehyde dehydrogenase, is used as an adjunct to behavioral modification
in the treatment of alcoholism since the unpleasant symptoms elicited by the accumulating acetaldehyde
are sufficient to dissuade further ethanol ingestion. Monoamine oxidase inhibitors are available
as drugs for the treatment of depression. If chemicals (e.g., tyramine) normally adequately metabolized
by these enzymes are ingested simultaneously, they may accumulate to a sufficient concentration to
cause severe toxicity (hypertensive crisis). Esterases where the active center contains a serine residue
are readily inhibited by organophosphates and carbamates. Such inhibition results in the accumulation
of other chemicals undergoing hydrolysis, particularly the endogenous substrate, acetylcholine, to the
point of toxicity.
Other Factors Responsible for Variations in Xenobiotic Metabolizing Enzymes
Animal 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 understanding
of species selective toxicities. Rodents have higher cytochrome P450 concentrations than other
mammalian species, birds, and fish. Among mammals, cats are particularly deficient in UDP-glucuronosyltransferase
activities and fish are deficient in all conjugations. This latter point has been
attributed to the lesser need of aquatic animals to render foreign compounds to their most water-soluble
form, since the volume of water that xenobiotics can diffuse into via the gills compensates for the lower
partition coefficient. In comparison to most laboratory animal species, the rat is well endowed with
sulfotransferase activity, a little lower in cytochrome P450 concentration, and relatively deficient in
glutathione transferase activity (Table 3.8).
TABLE 3.8 Species and Strain Variations in Xenobiotic-Metabolizing Enzymes a
Phase I Phase II
UGT
Species and Strain P450
pNA
deM GT1 GT2 GST ST
(vs. Male Sprague–Dawley Rat)
Rabbit b
140 — 250 275 575 140
Hamster 160 300 155 235 470 25
Rat: Fischer 90 125 115 115 55 —
Rat: Gunn 125 — 30 120 — —
Mouse: D2 85 245 60 170 225 320
Mouse: B6 — 85 325 90 325 235
Mouse: CF-1 120 490 — — 265 —
Mouse: SW b
105 — 65 220 200 50
Guinea pig b
105 — 180 95 415 30
Cat b
60 — 5 50 75 50
Dog b
70 — 335 355 85 30
Quail b
45 — 220 25 75 35
Trout b
68 — 5 20 60 10
a 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).