Selective suppression of rat hepatic cytochrome P450 2C11 by chloramphenicol.
Chloramphenicol produces mechanism-based inactivation of several rat hepatic microsomal P450 enzymes including 2C6, 2C11, 2B1/2 and 3A1/2. A preliminary study by this laboratory reported that 48 hr after in vivo treatment with chloramphenicol (CAP) 2C11 activity remained low, whereas activities catalyzed by 3A2 and 2C6 were almost fully restored (Halpert et al., Biochem. Pharmacol. 37: 3046-3048, 1988). Therefore, in experiments conducted to examine whether CAP affects P450 expression, Sprague-Dawley (SD) rats were treated with CAP (single i.p. injection, 300 mg/kg) and sacrificed at various times post-treatment. The loss of P450 2C6, 2C11 and 3A2 catalytic activities which is characteristic of inactivation was demonstrated 1 hr after CAP administration. However, at 4 and 6 days, 2C11-mediated progesterone 2 alpha-hydroxylase activity remained diminished by 52 and 45%, respectively. Similar decreases in anti-P450 2C11-reactive protein and 2C11 mRNA were observed at 6 days, suggesting that the compound acts at a pretranslational step. Evaluation of 2C11 regulators indicated that CAP causes a decrease in plasma thyroxine level in proportion to the loss of 2C11 activity, whereas testosterone appears to be unaffected. To minimize intragroup variability, the inbred Fischer 344 strain was then examined at 2 and 6 days after CAP treatment. Surprisingly, CAP caused no loss in 2C11 protein, although the compound does inactivate 2C11 in liver microsomes from Fischer 344 rats. These results suggest that CAP alters P450 expression in a manner distinct from previously described compounds.
Kraner
J C
JC
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson.
Morgan
E T
ET
Halpert
J R
JR
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D002701:Chloramphenicol / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013739:Testosterone / Q000097:blood; D013974:Thyroxine / Q000097:blood
D065607:Cytochrome P-450 Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D013739:Testosterone; D002701:Chloramphenicol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D013974:Thyroxine