REGULATION OF HEPATIC CYP1A ISOZYMES BY PIPERONYL BUTOXIDE AND ACENAPHTHYLENE IN THE MOUSE

The regulation of CYP1A1 and CYP1A2 isozymes by piperonyl butoxide (PB O) and acenaphthylene (ACN) was studied in the liver of male C57BL/6 a nd DBA/2 mice. These two cytochrome P450 genes are known to be regulat ed by the aromatic hydrocarbon-responsive receptor (AHR), however, it has been suggested that CYP1A2 is also induced by an AHR-independent m echanism. In this study, PBO induced hepatic CYP1A1 considerably more in C57BL/6 (Ahr(b-1)) than in DBA/2 (Ahr(d)) mice. In addition, the su perinduction of CYP1A1 in wildtype hepa1c1c7 cells, which is AHR-depen dent, resulted from PBO and cycloheximide treatment of the cells, In o ther studies in this laboratory using AHR knock-out (AHR(-/-)) mice, a hybrid of 129/SV and C57BL/6 strains, no induction of CYP1A1 occurred with PBO or ACN. [D.-Y. Ryu, P.E. Levi, P. Fernandez-Salguero, F.J. G onzalez, E. Hodgson, Mol. Pharmacol., 50 (1996) 443-346.] ACN, however , did not induce CYP1A1 tinder the experimental conditions used. These results suggest that PBO, but not ACN, induces CYP1A1 through a weak activation of AHR. On the other hand: hepatic CYP1A2 mRNA and hnRNA we re induced by PBO in both C57BL/6 and DBA/2 strains, but were not indu ced by ACN, a strong inducer of CYP1A2 in the B6C3F1 strain. However, both PBO and ACN induced CYP1A2 in AHF(-/-) mice. It is assumed, there fore, that the transcriptional induction of CYP1A2 by PBO and ACN is A HR-independent. In addition,the induction of CYP1A2 by ACN depends upo n the strain of mice. Immunohistochemical studies for CYP1A1/CYP1A2 ap oproteins showed that PBO induced CYP1A1/CYP1A2 around the central vei ns as did 3-methylcholanthrene (3-MC). The induction of CYP1A1/CYP1A2 by ACN, however, was not observed. consistent with the northern blot r esults. (C) 1997 Elsevier Science Ireland Ltd.