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.

2.50
Hdl Handle:
http://hdl.handle.net/10146/65240
Title:
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.
Authors:
Stuchal, Leah D.; Kleinow, Kevin M.; Stegeman, John J.; James, Margaret O.
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 microM (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 microM 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 microM 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 alpha-naphthoflavone all decreased the production of OH-MXC in liver microsomes, whereas alpha-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.
Citation:
Drug Metab. Dispos. 2006, 34 (6):932-938
Journal:
Drug metabolism and disposition: the biological fate of chemicals
Issue Date:
Jun-2006
URI:
http://hdl.handle.net/10146/65240
DOI:
10.1124/dmd.105.009068
PubMed ID:
16510540
Additional Links:
http://dmd.aspetjournals.org/cgi/content/full/34/6/932
Type:
Article
Language:
en
Description:
KEYWORDS CLASSIFICATION: Animals;Carbon;Carbon Radioisotopes;Carcinogens;Cytochrome P-450 CYP1A1;Cytochrome P-450 CYP3A;Dealkylation;Drug Interactions;enzymology;Endocrine Disruptors;Enzyme Induction;Female;Ictaluridae;Insecticides;Intestines;Kinetics;Liver;metabolism;Male;mechanisms of carcinogenesis;Methoxychlor;Methylcholanthrene;Microsomes,Liver;Phenols;Radioisotopes;Research;secondary;standards;toxicity;United States.
ISSN:
0090-9556
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorStuchal, Leah D.-
dc.contributor.authorKleinow, Kevin M.-
dc.contributor.authorStegeman, John J.-
dc.contributor.authorJames, Margaret O.-
dc.date.accessioned2009-04-17T12:20:40Z-
dc.date.available2009-04-17T12:20:40Z-
dc.date.issued2006-06-
dc.identifier.citationDrug Metab. Dispos. 2006, 34 (6):932-938en
dc.identifier.issn0090-9556-
dc.identifier.pmid16510540-
dc.identifier.doi10.1124/dmd.105.009068-
dc.identifier.urihttp://hdl.handle.net/10146/65240-
dc.descriptionKEYWORDS CLASSIFICATION: Animals;Carbon;Carbon Radioisotopes;Carcinogens;Cytochrome P-450 CYP1A1;Cytochrome P-450 CYP3A;Dealkylation;Drug Interactions;enzymology;Endocrine Disruptors;Enzyme Induction;Female;Ictaluridae;Insecticides;Intestines;Kinetics;Liver;metabolism;Male;mechanisms of carcinogenesis;Methoxychlor;Methylcholanthrene;Microsomes,Liver;Phenols;Radioisotopes;Research;secondary;standards;toxicity;United States.en
dc.description.abstractExposure 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 microM (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 microM 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 microM 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 alpha-naphthoflavone all decreased the production of OH-MXC in liver microsomes, whereas alpha-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.en
dc.language.isoenen
dc.relation.urlhttp://dmd.aspetjournals.org/cgi/content/full/34/6/932en
dc.subject.meshAnimals-
dc.subject.meshCarbon Radioisotopes-
dc.subject.meshCarcinogens-
dc.subject.meshCytochrome P-450 CYP1A1-
dc.subject.meshCytochrome P-450 CYP3A-
dc.subject.meshDealkylation-
dc.subject.meshDrug Interactions-
dc.subject.meshEndocrine Disruptors-
dc.subject.meshEnzyme Induction-
dc.subject.meshFemale-
dc.subject.meshIctaluridae-
dc.subject.meshInsecticides-
dc.subject.meshIntestines-
dc.subject.meshKinetics-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMethoxychlor-
dc.subject.meshMethylcholanthrene-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshPhenols-
dc.titleDemethylation 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.en
dc.typeArticleen
dc.identifier.journalDrug metabolism and disposition: the biological fate of chemicalsen
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