PRINCIPLES OF TOXICOLOGY

TABLE 3.6 Changes in Rat Hepatic Drug-Metabolizing Enzymes Following Xenobiotic Administration a
Dose
(mg/kg × CYT
UGT GST ST
Agent (use)
days) P450 (pNP) GT1 (N) GT2 (M)
(% control)
(CDNB) (pNP)
SKF 525-A 80 × 4 400 b
— 65 150 — —
1-Benzylmidazole 75 × 3 320 c
305 240 240 225 70
Troleandomycin (antibiotic) 500 × 4 300 b
— 100 200 — —
Clotrimazole (antifungal) 75 × 3 290 b
120 120 225 265 85
Phenobarbital (anticonvulsant) 80 × 4 265 130 127 455 155 50
Dexamethasone (glucocorticoid) 100 × 3 245 70 80 155 125 60
3-Methylcholanthrene d
20 × 4 215 185 300 155 145 90
PCBs (Aroclor 1254) (transformer
fluid)
25 × 6 205 265 270 280 140 110
2,3,6,7-Tetrachlorodibenzodioxin
(TCDD) d
0.01 × 1 185 185 295 115 140 90
4,4″-Dipyridyl 75 × 3 190 245 130 225 130 90
Fluconazole (antifungal) 75 × 3 180 c
180 175 170 130 115
Pregnenolone 16α carbonitrile d
75 × 4 180 85 100 150 140 120
Clofibrate (antihypertriglyceridemic) 400 × 3 180 65 80 85 95 —
trans-Stibene oxide d
400 × 4 175 170 195 260 215 100
5,6-Naphthoflavone [BNF] 80 × 3 165 495 250 130 185 85
Benzo(a)pyrene d
20 × 4 — 165 165 110 — —
Miconazole (antifungal) 150 × 3 150 165 140 95 155 100
Phenytoin (anticonvulsant) 100 × 7 150 110 — — — —
Carbamazepine (anticonvulsant) 100 × 7 145 125 — — — —
Tioconazole (antifungal) 150 × 3 130 c
300 215 330 170 70
Ketoconazole (antifungal) 150 × 4 130 c
150 110 175 100 70
Isosafrole d
150 × 4 120 150 160 205 180 100
7,8-Benzoflavone d
100 × 4 125 120 110 — —
Isoniazid (antitubercular) 100 × 4 105 e
60 80 120 95 90
1,10-Phenanthroline 75 × 3 105 105 100 105 85 105
Cimetidine (antiulcer) 350 × 3 100 95 85 95 95 120
3,4 Benzoquinoline 75 × 3 90 230 240 320 140 80
Butylated hydroxyanisole
(antioxidant) d
500 × 10 85 150 145 145 155 90
2,2′-Dipyridyl 75 × 3 85 310 205 235 145 80
Chloramphenicol (antibiotic) 300 × 3 80 95 90 125 105 70
Cyclosporine (immunosuppressant) 25 × 10 80 — 130 100 90 100
4,7-Phenanthroline 75 × 3 80 390 250 275 130 65
a
Abbreviations: Enzymes: UGT = UDP-glucuronosyltransferase, GST = glutathione S-transferase, ST = sulfotransferase.
Substrates: pNP = p-nitrophenol, N = 1-naphthol, M = morphine, CDNB = 1-chloro-2,4-dinitrobenzene.
b
Full detection requires prior destruction of metabolic intermediate complex.
c
Full detection requires time-dependent displacement of azole ligand by CO.
d
From Watkins JB, Gregus Z, Thompson TN, Klaassen CD, Toxicol. Appl. Pharmacol. 64: 439 (1982); Thompson TN, Watkins
JB, Gregus Z, Klaassen CD, Toxicol. Appl. Pharmacol. 66: 400 (1982).
e
Induction of P4502E isozyme (see Table 3.3) obscured by decreases in other forms.
Phase II; Glutathione Conjugation
3.2 BIOTRANSFORMATION REACTIONS 73
Conjugation with glutathione (γ-glutamylcysteinylglycine) is an important reaction for sequestering
reactive (toxic) metabolites, which may be generated by cytochrome P450 oxidations. Glutathione