Effects of cytochrome P-450 monooxygenase inducers on mouse hepatic microsomal metabolism of testosterone and alkoxyresorufins.
The effects of treatment with phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3-MC) and isosafrole on the hepatic microsomal formation of nine monohydroxy metabolites of testosterone and the O-dealkylation of the ethyl and pentyl ethers of resourfin were evaluated in adult male C57BL/6J and DBA/2NCR mice. In both strains, phenobarbital, TCPOBOP and PCN induced testosterone 2 beta-, 6 beta-, 15 beta- and 16 beta-hydroxylases up to 5-fold, while phenobarbital and TCPOBOP increased the rate of dealkylation of pentoxyresorufin by approximately 30-fold. However, phenobarbital and TCPOBOP did not exhibit identical patterns of induction for the testosterone oxidation reactions. Hepatic microsomes from C57BL/6J mice treated with TCPOBOP displayed a depression in 6 alpha-testosterone hydroxylase activity, which was also observed in PCN-treated animals, whereas phenobarbital-treated mice exhibited an elevation in this monooxygenase activity. A dose of TCPOBOP (0.5 mumol/kg) previously demonstrated to represent an ED50 for mouse aminopyrine N-demethylase activity was also found to approximate the ED50 for pentoxyresorufin O-dealkylase activity in the C57BL/6J mouse. Isosafrole or 3-MC treatment had little effect on testosterone metabolism or pentoxyresorufin O-dealkylase activity in either strain, while 3-MC induced ethoxyresorufin O-deethylase activity in C57BL/6J but not DBA/2NCR mice. This study confirms that TCPOBOP is a potent cytochrome P-450 inducer which most closely resembles phenobarbital in its mode of action. However, TCPOBOP and phenobarbital do not evoke identical modulations of cytochrome P-450-dependent monooxygenases in mice.
Kelley
M
M
Department of Veterinary Physiology, Texas A&M University, College Station 77843.
Womack
J
J
Safe
S
S
D000818:Animals; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012451:Safrole / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism*
D010078:Oxazines; D011725:Pyridines; D011285:Pregnenolone Carbonitrile; D013739:Testosterone; D008748:Methylcholanthrene; C014180:resorufin; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital