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DEMETHYLATION OF THE PESTICIDE METHOXYCHLOR IN LIVER AND INTESTINE FROM UNTREATED, METHOXYCHLOR-TREATED, AND 3-METHYLCHOLANTHRENE-TREATED CHANNEL CATFISH (ICTALURUS PUNCTATUS): EVIDENCE FOR ROLES OF CYP1 AND CYP3A FAMILY ISOZYMES

Department of Medicinal Chemistry, University of Florida, Gainesville, Florida (L.D.S., M.O.J.); Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana (K.M.K.); and Biology Department, Woods Hole Oceanographic Institute, Woods Hole, Massachusetts (J.J.S.)

Exposure to the organochlorine pesticide methoxychlor (MXC) is associated with endocrine disruption in several species through biotransformation to mono-desmethyl-MXC (OH-MXC) and bis-desmethyl-MXC (HPTE), which interact with estrogen receptors. The biotransformation of [¹⁴C]methoxychlor was examined in channel catfish (Ictalurus punctatus), a freshwater species found in the southern United States. Hepatic microsomes formed OH-MXC and HPTE, assessed by comigration with authentic standards. The K_m for OH-MXC formation by control liver microsomes was 3.8 ± 1.3 µM (mean ± S.D., n = 4), and V_max was 131 ± 53 pmol/min/mg protein. These values were similar to those of catfish pretreated with 2 mg/kg methoxychlor i.p. for 6 days (K_m 3.3 ± 0.8 µM and V_max 99 ± 17 pmol/min/mg) but less (p < 0.05) than the kinetic parameters for catfish treated with 3-methylcholanthrene (3-MC), which had K_m of 6.0 ± 1.1 µM and V_max of 246 ± 6 pmol/min/mg protein. Liver microsomes from 3-MC-treated fish produced significantly more of the secondary metabolite and more potent estrogen, HPTE. Intestinal microsomes formed OH-MXC at lower rates than liver. Methoxychlor pretreatment significantly reduced intestinal metabolite formation from 32 ± 4 to 15 ± 6 pmol/min/mg (mean ± S.D., n = 4), whereas 3-MC treatment significantly increased OH-MXC production to 72 ± 22 pmol/min/mg. Ketoconazole, clotrimazole, and -naphthoflavone all decreased the production of OH-MXC in liver microsomes, whereas -naphthoflavone stimulated HPTE formation, suggesting that CYP1 and CYP3 family isozymes demethylated methoxychlor. The results suggest that the formation of estrogenic metabolites from methoxychlor would be more rapid in catfish coexposed to CYP1 inducers.

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