2-Methoxy-4-nitroaniline and its isomers induce cytochrome P4501A (CYP1A) enzymes with different selectivities in the rat liver

• Published in: Biochimica et biophysica acta Vol. 1379; no. 3; pp. 391 - 398
• Main Authors: Degawa, Masakuni, Nakayama, Masafumi, Konno, Yoshihiro, Masubuchi, Kazuhiro, Yamazoe, Yasushi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 02.03.1998
• Subjects: 2-Methoxy-4-nitroaniline; Aniline Compounds - pharmacology; Animals; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P4501A; Enzyme Activation - drug effects; Enzyme induction; Enzyme Induction - drug effects; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Nitro Compounds - pharmacology; Rat liver; Rats; Rats, Inbred F344; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; 4-MeO-2-NA, 4-methoxy-2-nitroaniline; 3-NAS, 3-nitroanisole; 2-MeO-4-NA, 2-methoxy-4-nitroaniline; 2-MeO-5-NA, 2-methoxy-5-nitroaniline; Rat liver; Enzyme induction; 2-Methoxy-4-nitroaniline; 2-OH-4-NA, 2-hydroxy-4-nitroaniline; Cytochrome P4501A; CYP1A2, cytochrome P4501A2; 2-MeO-A, 2-methoxy-aniline; 4-NA, 4-nitroaniline
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/S0304-4165(97)00118-9

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.