Cytochrome P450 catalyzed covalent binding of methoxychlor to rat hepatic, microsomal iodothyronine 5'-monodeiodinase, type I: does exposure to methoxychlor disrupt thyroid hormone metabolism?
The insecticide methoxychlor is estrogenic in birds and mammals and interferes with sexual development and reproduction, but it is not known whether this toxicity is due solely to its estrogenicity. We now have found that during hepatic, microsomal metabolism of [ring-14C]- or [3H-OCH3]methoxychlor, their metabolite primarily binds to iodothyronine 5'-monodeiodinase, type I (5'-ID1). The purified, radiolabeled protein reacted with antibodies against protein disulfide isomerase, isoform Q5, which is highly homologous to 5'-ID1. Sequencing of the radiolabeled tryptic peptide indicated that methoxychlor bound to cysteine 372 or 375 or to lysine 376 of 5'-ID1. Treatment of rats with methoxychlor for 4 days decreased hepatic, microsomal 5'-ID1 activity from 2.94 to 2.20 nmol/min-mg prot (P < 0.02). Since 5'-ID1 catalyzes thyroxine conversion to the biologically active triiodothyronine, these data suggest that methoxychlor may interfere with thyroid hormone metabolism. This may be an additional factor in its environmental toxicity.
Zhou
L X
LX
Department of Pharmacology, School of Public Health, University of Minnesota, Minneapolis 55455, USA.
Dehal
S S
SS
Kupfer
D
D
Morrell
S
S
McKenzie
B A
BA
Eccleston
E D
ED
Holtzman
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity; D007306:Insecticides / Q000378:metabolism* / Q000633:toxicity; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D007535:Isomerases / Q000235:genetics; D008297:Male; D008731:Methoxychlor / Q000378:metabolism* / Q000633:toxicity; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D019704:Protein Disulfide-Isomerases; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D013963:Thyroid Hormones / Q000378:metabolism*
D004785:Environmental Pollutants; D007306:Insecticides; D013963:Thyroid Hormones; D003577:Cytochrome P-450 Enzyme System; D007453:Iodide Peroxidase; D007535:Isomerases; D019704:Protein Disulfide-Isomerases; D008731:Methoxychlor