SELECTIVE SUPPRESSION OF RAT HEPATIC CYTOCHROME-P450 2C11 BY CHLORAMPHENICOL

Chloramphenicol produces mechanism-based inactivation of several rat h epatic microsomal P450 enzymes including 2C6, 2C11, 2B1/2 and 3A1/2. A preliminary study by this laboratory reported that 48 hr after in viv o treatment with chloramphenicol (CAP) 2C11 activity remained low, whe reas activities catalyzed by 3A2 and 2C6 were almost fully restored (H alpert 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. Howev er, at 4 and 6 days, 2C11-mediated progesterone 2 alpha-hydroxylase ac tivity remained diminished by 52 and 45%, respectively. Similar decrea ses 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, whe reas testosterone appears to be unaffected. To minimize intragroup var iability, the inbred Fischer 344 strain was then examined at 2 and 6 d ays after CAP treatment. Surprisingly, CAP caused no loss in 2C11 prot ein, although the compound does inactivate 2C11 in liver microsomes fr om Fischer 344 rats. These results suggest that CAP alters P450 expres sion in a manner distinct from previously described compounds.