Vol. 294, Issue 1, 308-312, July 2000

Effect of Methoxychlor Administration to Male Rats on Hepatic, Microsomal Iodothyronine 5'-Deiodinase, Form I¹

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

Division of Environmental and Occupational Health, School of Public Health (S.L.H.), Departments of Pharmacology (J.L.H.), Medicine (J.L.H.), and Biochemistry (J.A.F.), University of Minnesota, Minneapolis; and Medical Service, Veterans Affairs Medical Center, Minneapolis, Minnesota (J.L.H.)

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 × 10³ (controls) to 0.99 ± 0.09 × 10³ (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.