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First published on March 1, 2006; DOI: 10.1124/dmd.105.009068

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Received for publication December 21, 2005.
Revised February 22, 2006.
Accepted for publication February 23, 2006.

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 3A family isozymes

Leah D. Stuchal 1, Kevin M. Kleinow 2, John J. Stegeman 3, Margaret O. James 4*

1 University of Florida 2 Louisiana State University 3 Woods Hole Oceanographic Institution 4 University of Florida College of Medicine

* Address correspondence to: E-mail: mojames{at}ufl.edu

Abstract

Exposure to the organochlorine pesticide methoxychlor 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 co-migration with authentic standards. The Km for OH-MXC formation by control liver microsomes was 3.8 ± 1.3 mM (mean ± S.D., n = 4) and Vmax was 131 ± 53 pmol/min/mg protein. These values were similar to those of catfish pretreated with 2 mg methoxychlor /kg ip, for 6 days (Km 3.3 ± 0.8 mM and Vmax 99 ± 17 pmol/min/mg), but lower (p<0.05) than the kinetic parameters for catfish treated with 3-methylcholanthrene (3-MC), which had Km of 6.0 ± 1.1 µM and Vmax 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) while 3-MC treatment significantly raised OH-MXC production to 72 ± 22 pmol/min/mg. Ketoconazole, clotrimazole and {alpha}-naphthoflavone all decreased the production of OH-MXC in liver microsomes, while {alpha}-naphthoflavone stimulated HPTE formation, suggesting CYP1 and CYP3 family isozymes demethylated methoxychlor. The results suggest that the formation of estrogenic metabolites from methoxychlor would be more rapid in catfish co-exposed to CYP1 inducers.


Key words: cytochrome P450 catalyzed oxidations, environmental toxicology, fish cytochrome P450, insecticides, monooxygenases




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