Multiple cytochrome P-450 subfamilies are co-induced with P-glycoprotein by both phenothiazine and 2-acetylaminofluorene in rats

We studied the effects of two P-glycoprotein (P-gp) inducers, 2-acetylamino fluorene (2-AAF) and phenothiazine (PTZ), administered intraperitoneally, o n the activities and content of hepatic cytochrome P-450 (CYP) subfamilies in hepatic microsomes of Sprague-Dawley rats. After 4-day administration of 2-AAF or PTZ, the P-gp content was increased. The total CYP content after PTZ treatment was significantly increased compared with that of controls. T he CYP1A, CYP2B and CYP3A2 contents were induced, while the CYP2C6, CYP2C11 and CYP2E1 contents remained unaffected. A marked increase in CYP1A1 was f ound after administration of each compound. Ethoxyresorufin O-deethylase, p entoxyresorufin O-deethylase and testosterone 6 beta hydroxylation activiti es showed a significant increase after both 2AAF and PTZ treatments. In par ticular, ethoxyresorufin O-deethylase exhibited more than ten times greater activity than that of the controls after the treatments. These results sug gest that P-gp inducers affect several CYP subfamilies in addition to CYP3A , which is reported to be up-regulated coordinately with P-gp by a CYP3A in ducer. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.