PRINCIPLES OF TOXICOLOGY

TABLE 3.7 Induction of Xenobiotic-Metabolizing Enzymes in Males of Various Animal Species a
tal-induced increases in cytochrome P450, glutathione S-transferase, and preferential increase in GT2
UDP-glucuronosyltransferase activity over GT1 UDP-glucuronosyltransferase activity are similar in
hamster and rat. Similarly, phenobarbital does not increase sulfotransferase activity in either species.
β-Naphthoflavone, a polycyclic hydrocarbon-type inducer, has a similar effect in rat, mouse, and
hamster, although the effect in the mouse depends on the strain employed. Two strains (CF-1 and D2)
are considered nonresponsive with respect to induction by polycyclic hydrocarbon induction, and for
these, in comparison with a B6 strain, there is no increase in cytochrome P450 nor induction of the
GT1 UDP-glucuronosyltransferase. Dexamethasone produces large increases in cytochrome P450
with only minor increases in GT1 and GT2 UDP-glucuronosyltransferases and glutathione-S-transferases
in either rat or mouse.
Inhibition of Xenobiotic-Metabolizing Enzymes
3.2 BIOTRANSFORMATION REACTIONS 77
Phase I Phase II
P450 GT1 GT2 GST ST
Inducing Agent Species and Strain
(% of naive
animal)
Ethanol Rat: Fischer 125 140 115 175 90
Rabbit: NZW — 147 172 — —
Phenobarbital Rat: Sprague–Dawley 235 125 420 210 105
Hamster: Syrian 160 120 220 120 80
Mouse: CF-1 185 — — 135 —
Rabbit: NZW — 110 155 — —
B-Naphthoflavone Rat: Sprague–Dawley 160 155 130 150 85
Mouse: CF-1 85 — — 75 —
Mouse: D2 105 105 115 110 —
Mouse B6 270 145 140 125 —
Hamster: Syrian 145 — — 65 —
Rabbit: NZW — 115 170 — —
Dexamethasone Rat: Sprague–Dawley 245 80 155 140 30
Mouse: CF-1 240 — — 100 —
Mouse D2 280 100 60 80 160
Hamster: Syrian 75 — — 155 —
a
Abbreviations: UGT = UDP-glucuronosyltransferase (two isozymes, GT1 and GT2); GST = glutathione S-transferase; ST =
sulfotransferase; NZW = New Zealand White.
Since the body contains numerous but relatively nonspecific enzymes to metabolize xenobiotics, many
chemicals compete for the same enzymes and mutually inhibit the metabolism of each. This may or
may not be of great consequence, depending on whether the activity of xenobiotic-metabolizing
enzymes is rate limiting. In considering inhibitors, and their beneficial or adverse effects, it is important
to consider the perspective from which it is viewed. Piperonyl butoxide is used to inhibit insect
cytochrome P450 so that the insect does not metabolize and rid itself of the pesticide, thus increasing
(synergizing) the effectiveness of the pesticide. N-substituted imidazoles (e.g., clotrimazole) inhibit
cytochrome P450-dependent ergosterol biosynthesis in fungi and prevent growth. These beneficial
agents, if they inhibit human hepatic cytochrome P450 and slow the metabolism of other xenobiotics
(usually labeled as drug–drug interactions), are considered as acting in an adverse manner. Inhibition
UGT