Effect of 2,4,4'-trichloro-2'-hydroxydiphenyl ether on cytochrome P450 enzymes in the rat liver.
We examined the effect of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on microsomal cytochrome P450 (P450) enzymes in rat liver. Rats were treated intraperitoneally with Irgasan DP300 daily for 4 days, at doses of 0.2, 0.4 and 0.8 mmol/kg. Among the P450-dependent monooxygenase activities, 7-benzyloxyresorufin O-debenzylase (BROD) and 7-pentoxyresorufin O-depentylase (PROD) in rats, which are associated with CYP2B1, were remarkably induced by all doses of Irgasan DP300. The relative induction to each control activity were from 5.6- to 22.3-fold and 4.9- to 20.2-fold, respectively. Furthermore, immunoblotting showed that CYP2B1/2 protein level in rat liver microsomes was increased from 10.8- to 34.4-fold by Irgasan DP300. In addition, 7-ethoxycoumarin O-deethylase (ECOD) and p-nitrophenol hydroxylase (PNPH) activities were significantly increased by Irgasan DP300 at all doses (from 1.4- to 4.9-fold). Although the activities of other P450-dependent monooxygenases, namely aminopyrine N-demethylase (APND), aniline p-hydroxylase (ANPH), erythromycin N-demethylase (EMND), lauric acid omega-hydroxylase (LAOH) and testosterone 6 beta-hydroxylase (TS6BH) were increased at high doses (> or = 0.4 mmol/kg) of Irgasan DP300, the relative level was lower than those of the CYP2B1-dependent monooxygenases such as BROD and PROD. However, 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD), testosterone 2 alpha-hydroxylase (TS2AH) and testosterone 7 alpha-hydroxylase (TS7AH) activities were not affected by any doses of Irgsan DP300. Immunoblotting showed that CYP3A2/1 and CYP4A1 protein levels were significantly induced from 1.3- to 2.2-fold by Irgasan DP300 (> or = 0.4 mmol/kg), whereas those of CYP1A1/2, CYP2C11/6 and CYP2E1 were not affected by any doses of Irgasan DP300. These results suggest that Irgasan DP300 induces the P450 isoforms of CYP2B subfamily in the rat liver, and that the induced P450 isozymes closely relates to the toxicity of Irgasan DP300 or its chlorinated derivatives.
Hanioka
N
N
Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Jinno
H
H
Nishimura
T
T
Ando
M
M
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis; D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis; D000815:Aniline Hydroxylase / Q000096:biosynthesis; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D051544:Cytochrome P-450 CYP3A; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004987:Ethers / Q000008:administration & dosage / Q000633:toxicity*; D015151:Immunoblotting; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D014260:Triclosan
D000891:Anti-Infective Agents, Local; D004987:Ethers; D007527:Isoenzymes; D014260:Triclosan; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D015660:7-Alkoxycoumarin O-Dealkylase; D019392:Cytochrome P-450 CYP2E1; D000815:Aniline Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D042926:Cytochrome P-450 CYP4A; D010089:Oxidoreductases, N-Demethylating; D000633:Aminopyrine N-Demethylase