Abstract
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 Km for OH-MXC formation by control liver microsomes was 3.8 ± 1.3 μM (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/kg methoxychlor i.p. for 6 days (Km 3.3 ± 0.8 μM and Vmax 99 ± 17 pmol/min/mg) but less (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 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 α-naphthoflavone all decreased the production of OH-MXC in liver microsomes, whereas α-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.
Footnotes
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This publication was made possible by Grant 5P42 ES07375 from the National Institute of Environmental Health Sciences, National Institutes of Health (NIEHS, NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. Portions of this work were presented at the 12th International Symposium on Pollutant Responses in Marine Organisms, May 2003, abstract published in Marine Environmental Research 58:540-541, 2004; and the 8th International Meeting of the International Society for the Study of Xenobiotics, August 2004, abstract published in Drug Metab Rev36(Suppl 1):267.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.009068.
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ABBREVIATIONS: methoxychlor, [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane]; DDT, 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane; OH-MXC, mono-desmethyl-methoxychlor; HPTE, bis-desmethyl-methoxychlor; P450, cytochrome P450; 3-MC, 3-methylcholanthrene; EROD, ethoxyresorufin O-deethylation; PXR, pregnane X receptor.
- Received December 21, 2005.
- Accepted February 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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