| Description |
The metabolism of xenobiotics by extrahepatic cytochrome P450 (P450) may be integral in the development of organ-selective toxicities. Some xenobiotics also induce extrahepatic P450, and the polycyclic aromatic hydrocarbon (PAH)-type agents are generally considered the most effective inducers in the rat. N-benzylimidazole (NBI), induced rat hepatic P450 in a PAH-type manner; therefore, the effects of NBI and 15 other nitrogen heterocycles on P450 in rat kidney, lung and intestine were investigated. Those compounds that were high magnitude inducers of hepatic P450 also induced in some extrahepatic tissues, but, only two, NBI and N-methylnaphthylimidazole (NMN), induced in all four tissues. Induction was greater in kidney and intestine than in lung, but, except for induction by NBI and NMN, the degree did not approach that seen in liver. Several compounds induced extrahepatic P450 isozymes (determined by monooxygenase activities) that are not induced by PAHs, but interorgan inconsistencies in the extent and the pattern of isozyme induction were observed. Further investigations revealed that these interorgan inconsistencies in induction were probably not caused by the persistence of residual inhibitory nitrogen heterocycle, since evidence for the persistence of NBI in liver (inhibition of monooxygenase activities relative to P450, slowed development of CO-ferrous P450 spectra, and alteration of type II binding characteristics) and in extrahepatic tissues (alteration of type II binding characteristics) was not consistent with the degree of P450 induction by NBI in the tissues. The yield of hepatic, but not extrahepatic, microsomes was decreased by 30-40% by three compounds, including NBI. Further studies with NBI indicated that the decreased yield was due to an alteration of the sedimentation properties of hepatic subcellular organelles, which resulted in an increased loss of microsomes and mitochondria from liver homogenates during low-speed centrifugation. The ramifications of renal P450 induction by nitrogen heterocycles to the development of chloroform nephrotoxicity were investigated using a rat kidney slice model. The results of these and additional studies with other inducers and with P450 inhibitors were inconclusive, suggesting that the rat kidney slice model may not be valid when nephrotoxicity is thought to arise from reactive metabolites generated by P450. |
