METABOLISM OF METHOXYCHLOR BY HEPATIC-P-450 MONOOXYGENASES IN RAT AND HUMAN .1. CHARACTERIZATION OF A NOVEL CATECHOL METABOLITE

被引:35
作者
KUPFER, D [1 ]
BULGER, WH [1 ]
THEOHARIDES, AD [1 ]
机构
[1] WALTER REED ARMY MED CTR,WASHINGTON,DC 20307
关键词
D O I
10.1021/tx00013a002
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Previous investigations demonstrated that the incubation of the chlorinated hydrocarbon pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] with rat liver microsomes generates phenolic estrogenic metabolites. The current study shows that the incubation of liver microsomes from untreated and phenobarbital-treated rats and human donors, in the presence of NADPH, yields three phenolic metabolites. Identification of the metabolites was achieved by TLC, HPLC, GC/MS, and LC/MS and by hydrodynamic voltammetric analysis. These metabolites were identified as the mono- and didemethylated phenolic derivatives (mono-OH-M and bis-OH-M, respectively) and as a novel trihydroxy derivative (tris-OH-M). The tris-OH-M was demonstrated to be a catechol [1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3,4-dihydroxyphenyl) ethane]. Furthermore, the tris-OH-M becomes radiolabeled by [methyl-3H3]-Sadenosylmethionine (SAM) in a reaction catalyzed by catechol O-methyltransferase (COMT), indicating that tris-OH-M behaves like a catechol. Incubation of the monohydroxy metabolite with liver microsomes from phenobarbital-treated rats (PB microsomes) yields the dihydroxy and the trihydroxy metabolites. Furthermore, the time course of methoxychlor metabolism by PB microsomes demonstrated a rapid appearance and disappearance of the monohydroxy metabolite with the subsequent formation of the dihydroxy and trihydroxy metabolites. On the basis of these findings, it is proposed that the metabolic route of methoxychlor by monooxygenases involves sequential demethylations to the dihydroxy derivative and a subsequent ring hydroxylation. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:8 / 16
页数:9
相关论文
共 30 条
[1]  
BULGER WH, 1985, MOL PHARMACOL, V27, P115
[2]   STUDIES ON INVIVO AND INVITRO ESTROGENIC ACTIVITIES OF METHOXYCHLOR AND ITS METABOLITES ROLE OF HEPATIC MONO-OXYGENASE IN METHOXYCHLOR ACTIVATION [J].
BULGER, WH ;
MUCCITELLI, RM ;
KUPFER, D .
BIOCHEMICAL PHARMACOLOGY, 1978, 27 (20) :2417-2423
[3]  
BULGER WH, 1989, DRUG METAB DISPOS, V17, P487
[4]   INTERACTIONS OF METHOXYCHLOR, METHOXYCHLOR BASE-SOLUBLE CONTAMINANT, AND 2,2-BIS(PARA-HYDROXYPHENYL)-1,1,1-TRICHLOROETHANE WITH RAT UTERINE ESTROGEN-RECEPTOR [J].
BULGER, WH ;
MUCCITELLI, RM ;
KUPFER, D .
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH, 1978, 4 (5-6) :881-893
[5]   COVALENT BINDING OF [C-14]-LABELED METHOXYCHLOR METABOLITE(S) TO RAT-LIVER MICROSOMAL COMPONENTS [J].
BULGER, WH ;
TEMPLE, JE ;
KUPFER, D .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1983, 68 (03) :367-374
[6]   HYDROXYLATION OF TRANS-DELTA-1-TETRAHYDROCANNABINOL BY HEPATIC MICROSOMAL OXYGENASE [J].
BURSTEIN, S ;
KUPFER, D .
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1971, 191 (DEC31) :61-&
[7]   ANTIFERTILITY EFFECT OF METHOXYCHLOR IN FEMALE RATS - DOSE-DEPENDENT AND TIME-DEPENDENT BLOCKADE OF PREGNANCY [J].
CUMMINGS, AM ;
GRAY, LE .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1989, 97 (03) :454-462
[8]   METHOXYCHLOR INDUCES ESTROGEN-LIKE ALTERATIONS OF BEHAVIOR AND THE REPRODUCTIVE-TRACT IN THE FEMALE RAT AND HAMSTER - EFFECTS ON SEX BEHAVIOR, RUNNING WHEEL ACTIVITY, AND UTERINE MORPHOLOGY [J].
GRAY, LE ;
OSTBY, JS ;
FERRELL, JM ;
SIGMON, ER ;
GOLDMAN, JM .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1988, 96 (03) :525-540
[9]  
HAMILTON M, 1986, DRUG METAB DISPOS, V14, P5
[10]  
HAYES WJ, 1971, CLIN HDB EC POISONS