Acetaminophen analog N-acetyl-m-aminophenol, but not its reactive metabolite, N-acetyl-p-benzoquinone imine induces CYP3A activity via inhibition of protein degradation.
Cytochrome P450 (CYP) 3A subfamily members are known to metabolize various types of drugs, highlighting the importance of understanding drug-drug interactions (DDI) depending on CYP3A induction or inhibition. While transcriptional regulation of CYP3A members is widely understood, post-translational regulation needs to be elucidated. We previously reported that acetaminophen (APAP) induces CYP3A activity via inhibition of protein degradation and proposed a novel DDI concept. N-Acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP formed by CYP, is known to cause adverse events related to depletion of intracellular reduced glutathione (GSH). We aimed to inspect whether NAPQI rather than APAP itself could cause the inhibitory effects on protein degradation. We found that N-acetyl-l-cysteine, the precursor of GSH, and 1-aminobenzotriazole, a nonselective CYP inhibitor, had no effect on CYP3A1/23 protein levels affected by APAP. Thus, we used APAP analogs to test CYP3A1/23 mRNA levels, protein levels, and CYP3A activity. We found N-acetyl-m-aminophenol (AMAP), a regioisomer of APAP, has the same inhibitory effects of CYP3A1/23 protein degradation, while p-acetamidobenzoic acid (PAcBA), a carboxy-substituted form of APAP, shows no inhibitory effects. AMAP and PAcBA cannot be oxidized to quinone imine forms such as NAPQI, so the inhibitory effects could depend on the specific chemical structure of APAP.
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Masataka
M
Santoh
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. Electronic address: sanoh@hiroshima-u.ac.jp.
Seigo
S
Sanoh
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Yuya
Y
Ohtsuki
Molding Component Business Department, New Business Development Division, Kuraray Co., Ltd., 1-1-3 Otemachi, Chiyoda-ku, Tokyo, 100-8115, Japan.
Yoko
Y
Ejiri
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Yaichiro
Y
Kotake
Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Shigeru
S
Ohta
D000082:Acetaminophen / Q000378:metabolism / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000378:metabolism / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007097:Imines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D061251:Primary Cell Culture; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
D016227:Benzoquinones; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007097:Imines; D014230:Triazoles; C033020:1-aminobenzotriazole; D000082:Acetaminophen; D051544:Cytochrome P-450 CYP3A; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione; D000111:Acetylcysteine
Acetaminophen; Cytochrome P450; Hepatocyte; N-acetyl-m-aminophenol; Protein degradation; Spheroid