2-METHOXY-4-NITROANILINE AND ITS ISOMERS INDUCE CYTOCHROME P4501A (CYP1A) ENZYMES WITH DIFFERENT SELECTIVITIES IN THE RAT-LIVER

We reported previously that 2-methoxy-4-nitroaniline (2-MeO-4-NA) is a selective inducer of cytochrome P4501A2 (CYP1A2) in the rat liver, an d its molecular size is the smallest among known CYP1A2-selective indu cers. In the present study, a structure-activity relationship on the C YP1A2-selective induction has been investigated using isomeric nitroan i-sidines and their related chemicals, Western blot analyses revealed that the chemicals removed a substituent (amino, methoxyl or nitro gro up) from a 2-MeO-4-NA molecule had no capacity for inducing CYP1A enzy mes in rat livers. On the other hand, isomeric nitroanisidines such as 2-MeO-4-NA, 2-MeO-5-NA and 4-MeO-2-NA induced both CYP1A2 and CYP1A1 enzymes with different selectivities. As judged from the induced level s of CYP1A proteins, 2-MeO-4-NA (CYP1A2/CYP1A1 ratio; 9.5) and 4-MeO-2 -NA (0.3) were the most selective inducers of CYP1A2 and CYP1A1, respe ctively, among the isomeric nitroanisidines (0.44 mmol/kg) used. The i nduced level of CYP1A2 protein was in the order 2-MeO-4-NA > 2-MeO-5-N A > 4-MeO-2-NA, although no significant difference was observed on the ir CYP1A2 mRNA level. On the contrary, increases in the levels of CYP1 A1 mRNA and protein were in the order 4-MeO-2-NA > 2-MeO-5-NA > 2-MeO- 4-NA. The present findings indicate that all three substituents (amino , methoxyl and nitro groups) are necessary components of nitroanisidin es for induction of CYP1A enzymes, and also show that regio-isomeric p ositions of these substituents determine the selectivity in the induct ion of CYP1A enzymes. (C) 1998 Elsevier Science B.V.