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

We previously reported that methoxychlor administration inhibits the activi ty of the hepatic, microsomal iodothyronine 5'-deiodinase, form I (ID-I; Zh ou 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 iden tified as ID-I (Boado et al., 1988; Santini et al., 1992). This protein is 98% homologous to the thiol: protein disulfide oxidoreductase, form Q5 (ERp 55; Boado et al., 1988; Santini et al., 1992). Although at the time there w as some controversy, most studies now suggest that ID-I is actually catalyz ed 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 furt her examined the basis for the decreased ID-I activity observed after metho xychlor 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 signi ficant 15% decline in total hepatic, microsomal protein at all doses. The I D-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 pr otein 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 da ta suggest that the decreased ID-I observed with chronic methoxychlor admin istration was due to decreased transcription or stability of the mRNA encod ing the 27-kDa protein.