Sex difference in the principal cytochrome P-450 for tributyltin metabolism in rats.
Tributyltin is metabolized by cytochrome P-450 (CYP) system enzymes, and its metabolic fate may contribute to the toxicity of the chemical. In the present study, it is examined whether sex differences in the metabolism of tributyltin exist in rats. In addition, the in vivo and in vitro metabolism of tributyltin was investigated using rat hepatic CYP systems to confirm the principal CYP involved. A significant sex difference in metabolism occurred both in vivo and in vitro, suggesting that one of the CYPs responsible for tributyltin metabolism in rats is male specific or predominant at least. Eight cDNA-expressed rat CYPs, including typical phenobarbital (PB)-inducible forms and members of the CYP2C subfamily, were tested to determine their capability for tributyltin metabolism. Among the enzymes studied, a statistically significant dealkylation of tributyltin was mediated by CYP2C6 and 2C11. Furthermore, the sex difference in metabolism disappeared in vitro after anti-rat CYP2C11 antibody pretreatment because CYP2C11 is a major male-specific form in rats. These results indicate that CYP2C6 is the principal CYP for tributyltin metabolism in female rats, whereas CYP2C11 as well as 2C6 is involved in tributyltin metabolism in male rats, and it is suggested that CYP2C11 is responsible for the significant sex difference in the metabolism of tributyltin observed in rats.
Ohhira
Shuji
S
Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, Tochigi 321-0293, Japan. s-ohhira@dokkyomed.ac.jp
Enomoto
Mitsunori
M
Matsui
Hisao
H
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D018076:DNA, Complementary / Q000096:biosynthesis; D005260:Female; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase / Q000096:biosynthesis / Q000378:metabolism*; D013255:Steroid 21-Hydroxylase / Q000096:biosynthesis / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000493:pharmacokinetics*
D018076:DNA, Complementary; D014220:Trialkyltin Compounds; C011559:tributyltin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase