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, and its molecular size is the smallest among known CYP1A2-selective inducers. In the present study, a structure-activity relationship on the CYP1A2-selective induction has been investigated using isomeric nitroanisidines and their related chemicals. Western blot analyses revealed that the chemicals removed a substituent (amino, methoxyl or nitro group) from a 2-MeO-4-NA molecule had no capacity for inducing CYP1A enzymes 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 levels 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, respectively, among the isomeric nitroanisidines (0.44 mmol/kg) used. The induced level of CYP1A2 protein was in the order 2-MeO-4-NA > 2-MeO-5-NA > 4-MeO-2-NA, although no significant difference was observed on their CYP1A2 mRNA level. On the contrary, increases in the levels of CYP1A1 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 nitroanisidines for induction of CYP1A enzymes, and also show that regio-isomeric positions of these substituents determine the selectivity in the induction of CYP1A enzymes.
Degawa
M
M
Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Nakayama
M
M
Konno
Y
Y
Masubuchi
K
K
Yamazoe
Y
Y
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009574:Nitro Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D000814:Aniline Compounds; D009574:Nitro Compounds; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System