Sex-dependent regulation of hepatic cytochrome P-450 by DDT.
Dichlorodiphenyltrichloroethane (DDT) is a well-known inducer of microsomal monooxygenase systems in rodent liver. However, little information is available on its effects on the sex-dependent regulation of CYPs preferentially affected. Therefore, our objective was to evaluate the effects of DDT on the sexual expression pattern of some hepatic P-450 isozymes. Single doses of technical DDT (0, 0.1, 1, 5, 10, or 100 mg/kg body wt) were administered by gavage to Wistar rats. The effects on CYPs 1A1, 2B11/2B2, 2C11, 2E1, 3A1, and 3A2, were assessed 24 h later by means of CYP protein content determined by Western blotting and/or enzyme activities participating in alkoxyresorufin and pnitrophenol metabolism. The highest dose induced 18-fold the expression of CYP3A2 in female rats without producing significant induction (< 3-fold) in males. The effects on this isozyme, which is not normally expressed in females, suggest that DDT is able to modulate sexual metabolic dimorphism, as 3A2 expression is androgen dependent. DDT did not significantly alter CYP3A1 in males, suggesting that DDT is not a pure phenobarbital (PB)-type inducer. The effects on CYP2B1/2B2 protein (19-fold) and associated enzyme activities indicated that males had a lower response threshold than females, but that the latter were able to reach a higher relative induction. The preferential induction of CYPs 2B and 3A by DDT in a sex-related manner suggest that CYP regulation could play an important role in endocrine disruption.
Sierra-Santoyo
A
A
Departamento de Farmacología y Toxicología, CINVESTAV-IPN, Mexico DF, Mexico.
Hernández
M
M
Albores
A
A
Cebrián
M E
ME
D000818:Animals; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003634:DDT / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007202:Indicators and Reagents; D007306:Insecticides / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000096:biosynthesis
D007202:Indicators and Reagents; D007306:Insecticides; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C022657:steroid hormone 6-beta-hydroxylase