title: Acetaminophen induces accumulation of functional rat CYP3A via polyubiquitination dysfunction.
abstract: Acetaminophen (APAP) is extensively used as an analgesic and antipyretic drug. APAP is partly metabolized to N-acetyl-p-benzoquinone imine, a reactive metabolite, by cytochrome P450 (CYP) 1A2, 2E1 and 3A4. Some reports have indicated that CYP3A protein production and its metabolic activity are induced by APAP in rats in vivo. The CYP3A subfamily is believed to be transcriptionally regulated by chemical compounds. However, the mechanism underlying these responses is not completely understood. To clarify these mechanisms, we assessed the effects of APAP on CYP3A1/23 protein levels according to mRNA synthesis and protein degradation in rat hepatocyte spheroids, a model of liver tissue, in vivo. APAP induced CYP3A1/23 protein levels and metabolic activity. However, no change in CYP3A1/23 mRNA levels was observed. Moreover, APAP prolonged the half-life of CYP3A1/23 protein. CYP3A is known to be degraded via the ubiquitin-proteasome system. APAP significantly was found to decrease levels of polyubiquitinated CYP3A1/23 and glycoprotein 78, an E3 ligase of CYP3A1/23. These findings demonstrate that APAP induces accumulation of functional CYP3A protein via inhibition of protein degradation. Our findings may lead to the determination of novel drug-drug interactions with APAP.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Santoh
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Molding Component Business Department, New business Development Division, Kuraray Co., Ltd. 1-1-3 Otemachi, Chiyoda-ku, Tokyo, 100-8115, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ejiri
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects*; D025821:Polyubiquitin / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
chemical_list: D016227:Benzoquinones; D006023:Glycoproteins; D012333:RNA, Messenger; D025821:Polyubiquitin; D000082:Acetaminophen; C004532:quinone; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A