PRINCIPLES OF TOXICOLOGY - Biology East Borneo

3.2 BIOTRANSFORMATION REACTIONS 73TABLE 3.6 Changes in Rat Hepatic Drug-Metabolizing Enzymes Following Xenobiotic Administration aAgent (use)Dose(mg/kg ×days)CYTP450(pNP)UGT GSTGT1 (N) GT2 (M) (CDNB)(% control)ST(pNP)SKF 525-A 80 × 4 400 b — 65 150 — —1-Benzylmidazole 75 × 3 320 c 305 240 240 225 70Troleandomycin (antibiotic) 500 × 4 300 b — 100 200 — —Clotrimazole (antifungal) 75 × 3 290 b 120 120 225 265 85Phenobarbital (anticonvulsant) 80 × 4 265 130 127 455 155 50Dexamethasone (glucocorticoid) 100 × 3 245 70 80 155 125 603-Methylcholanthrene d 20 × 4 215 185 300 155 145 90PCBs (Aroclor 1254) (transformer 25 × 6 205 265 270 280 140 110fluid)2,3,6,7-Tetrachlorodibenzodioxin 0.01 × 185 185 295 115 140 90(TCDD) d 14,4″-Dipyridyl 75 × 3 190 245 130 225 130 90Fluconazole (antifungal) 75 × 3 180 c 180 175 170 130 115Pregnenolone 16α carbonitrile d 75 × 4 180 85 100 150 140 120Clofibrate (antihypertriglyceridemic) 400 × 3 180 65 80 85 95 —trans-Stibene oxide d 400 × 4 175 170 195 260 215 1005,6-Naphthoflavone [BNF] 80 × 3 165 495 250 130 185 85Benzo(a)pyrene d 20 × 4 — 165 165 110 — —Miconazole (antifungal) 150 × 3 150 165 140 95 155 100Phenytoin (anticonvulsant) 100 × 7 150 110 — — — —Carbamazepine (anticonvulsant) 100 × 7 145 125 — — — —Tioconazole (antifungal) 150 × 3 130 c 300 215 330 170 70Ketoconazole (antifungal) 150 × 4 130 c 150 110 175 100 70Isosafrole d 150 × 4 120 150 160 205 180 1007,8-Benzoflavone d 100 × 4 125 120 110 — —Isoniazid (antitubercular) 100 × 4 105 e 60 80 120 95 901,10-Phenanthroline 75 × 3 105 105 100 105 85 105Cimetidine (antiulcer) 350 × 3 100 95 85 95 95 1203,4 Benzoquinoline 75 × 3 90 230 240 320 140 80Butylated hydroxyanisole500 × 10 85 150 145 145 155 90(antioxidant) d2,2′-Dipyridyl 75 × 3 85 310 205 235 145 80Chloramphenicol (antibiotic) 300 × 3 80 95 90 125 105 70Cyclosporine (immunosuppressant) 25 × 10 80 — 130 100 90 1004,7-Phenanthroline 75 × 3 80 390 250 275 130 65a 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, WatkinsJB, 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 ConjugationConjugation with glutathione (γ-glutamylcysteinylglycine) is an important reaction for sequesteringreactive (toxic) metabolites, which may be generated by cytochrome P450 oxidations. Glutathione