Effect of methoxychlor administration to male rats on hepatic, microsomal iodothyronine 5'-deiodinase, form I

Shana L. Morrell, James A. Fuchs, Jordan L. Holtzman

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9 Scopus citations

Abstract

We previously reported that methoxychlor administration inhibits the activity of the hepatic, microsomal iodothyronine 5'-deiodinase, form I (ID- I; Zhou et al., 1995). Our data further suggested that the inhibition was due to the covalent binding of a methoxychlor metabolite to a 56-kDa protein identified as ID-I (Boado et al., 1988; Santini et al., 1992). This protein is 98% homologous to the thiol:protein disulfide oxidoreductase, form Q5 (ERp55; Boado et al., 1988; Santini et al., 1992). Although at the time there was some controversy, most studies now suggest that ID-I is actually catalyzed by a 27-kDa selenoprotein that does not form adducts with methoxychlor (Schoenmakers et al., 1989; Mandel et al., 1992; Zhou et al., 1995). Because the 27-kDa protein is considered to be ID-I instead of ERp55, we have further examined the basis for the decreased ID-I activity observed after methoxychlor administration. Male, 150- to 200-g Sprague-Dawley rats were given methoxychlor (0-100 mg/kg/day) in corn oil by gavage for 14 days. ID-I was determined by a thyronine-specific immunoassay. Treated rats showed a significant 15% decline in total hepatic, microsomal protein at all doses. The ID-I-specific activity showed a linear decrease with increasing log doses of methoxychlor. The maximum decrease was 42% at 100 mg/kg/day. The 27-kDa protein specific content declined 37%. In rats given methoxychlor the ratios of the 27-kDa protein mRNA to the 18S ribosomal RNA declined from 2.2 ± 0.27 x 10-3 (controls) to 0.99 ± 0.09 x 10-3 (100 mg/kg/day). These data suggest that the decreased ID-I observed with chronic methoxychlor administration was due to decreased transcription or stability of the mRNA encoding the 27-kDa protein.

Original languageEnglish (US)
Pages (from-to)308-312
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume294
Issue number1
StatePublished - Jul 1 2000

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