Mirex exposure inhibits the uptake of estradiol-17 beta(beta-D-glucuronide), taurocholate, and L-alanine into isolated rat hepatocytes.
The insecticides mirex and chlordecone have previously been found to suppress the biliary excretion of a wide variety of compounds. In the present studies, the effects of mirex, chlordecone, and phenobarbital on the uptake of two endogenous organic anions, estradiol-17 beta(beta-D-glucuronide) (E217G), an estrogen metabolite, taurocholate (TC), a common bile acid, and an essential amino acid, L-alanine (L-Ala) (0.5 mM), into isolated rat hepatocytes was investigated. Female Sprague-Dawley rats were orally dosed with mirex (12.5, 25, and 50 mg/kg) or chlordecone (6.25, 12.5, and 18.75 mg/kg) dissolved in corn oil for 3 days and isolated rat hepatocytes were prepared 2 days later. Rats were also dosed orally with phenobarbital (50 mg/kg on the first day and 80 mg/kg for the next 4 days) dissolved in distilled deionized water, and isolated hepatocytes were prepared on the sixth day. Mirex significantly reduced the uptake of both organic anions (0.5, 10, and 50 microM E2 17G; 10 microM TC) into hepatocytes by 40-70%, whereas chlordecone had no effect on their uptake. Mirex at 50 mg/kg significantly reduced the Vmax for the low- and high-affinity E217G uptake sites by 70% and decreased the Km for the low affinity uptake site by 60%. Mirex also significantly decreased the Vmax for TC uptake from 1.11 to 0.82 nmol/min/mg protein but had no effect on its Km (23.2 vs 22.9 microM). Mirex at 50 mg/kg was also found to reduce the uptake of 0.5 mM L-Ala by nearly 40%. Phenobarbital had no effect on the uptake of E217G (0.5 microM), TC (10 microM), or L-Ala (0.5 mM). Mirex treatment had no effect on hepatic plasma membrane Na+,K(+)- or Mg2(+)-ATPase activity. Neither mirex nor chlordecone at 50-100 microM had any effect on the uptake of 10 microM TC when added directly to hepatocytes from naive rats. These results indicate that mirex decreases the transport of organic anions and L-Ala across the basolateral domain of the hepatocyte in addition to its inhibitory effects on biliary excretion.
Graduate Center for Toxicology, University of Kentucky, College of Medicine, Lexington 40536.
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D000251:Adenosine Triphosphatases / Q000378:metabolism; D000409:Alanine / Q000493:pharmacokinetics*; D000818:Animals; D002478:Cells, Cultured; D007631:Chlordecone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008917:Mirex / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism; D013656:Taurocholic Acid / Q000493:pharmacokinetics*
D007306:Insecticides; D007473:Ion Channels; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D013656:Taurocholic Acid; D012964:Sodium; D000251:Adenosine Triphosphatases; D008274:Magnesium; D000409:Alanine; D007631:Chlordecone; D011188:Potassium; D010634:Phenobarbital; D008917:Mirex