Human superoxide dismutase 1 attenuates quinoneimine metabolite formation from mefenamic acid. (30th January 2021)

• Record Type: Journal Article
• Authors: Ogiso, Takuo; Fukami, Tatsuki; Zhongzhe, Cheng; Konishi, Keigo; Nakano, Masataka; Nakajima, Miki
• Is Part Of: Toxicology. Volume 448(2021)
• Publication Date: 2021-01-30
• Subjects: 1-ABT 1-aminobenzotriazole -- APAP acetaminophen -- AQ amodiaquine -- AQQI-SG AQ-quinoneimine glutathione conjugate -- BCA bicinchoninic acid -- CE collision energies -- CM carboxymethyl -- DEAE diethylaminoethyl -- DIC diclofenac -- DICQI-SG DIC-quinoneimine glutathione conjugate -- FFA flufenamic acid -- FFAQI-SG FFA-quinoneimine glutathione conjugate -- G6P glucose-6-phosphate -- G6PDH glucose-6-phosphate dehydrogenase -- GSH glutathione -- HLC human liver cytosol -- HLM human liver microsomes -- LAP lapatinib -- LAPQI-SG LAP-quinoneimine glutathione conjugate -- LC–MS/MS liquid chromatography-tandem mass spectrometry -- LDH lactate dehydrogenase -- MFA mefenamic acid -- MFAQI-SG MFA-quinoneimine glutathione conjugate -- MOI multiplicity of infection -- MRM multiple reaction monitoring -- NADP+ β-nicotinamide adenine dinucleotide phosphate -- NAPQI-SG APAP-glutathione conjugate -- NQO1 NAD(P)H:quinone oxidoreductase 1 -- NPR NADPH-P450 oxidoreductase -- NSAIDs non-steroidal anti-inflammatory drugs -- P450 cytochrome P450 -- SOD1 superoxide dismutase 1 -- TFA tolfenamic acid -- TFAQI-SG TFA-quinoneimine glutathione conjugate; Mefenamic acid -- Quinoneimine -- SOD1 -- Cytotoxicity -- Superoxide; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152648
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Mefenamic acid (MFA), one of the nonsteroidal anti-inflammatory drugs (NSAIDs), sometimes causes liver injury. Quinoneimines formed by cytochrome P450 (CYP)-mediated oxidation of MFA are considered to be causal metabolites of the toxicity and are detoxified by glutathione conjugation. A previous study reported that NAD(P)H:quinone oxidoreductase 1 (NQO1) can reduce the quinoneimines, but NQO1 is scarcely expressed in the human liver. The purpose is to identify enzyme(s) responsible for the decrease in MFA-quinoneimine formation in the human liver. The formation of MFA-quinoneimine by recombinant CYP1A2 and CYP2C9 was significantly decreased by the addition of human liver cytosol, and the extent of the decrease in the metabolite formed by CYP1A2 was larger than that by CYP2C9. By column chromatography, superoxide dismutase 1 (SOD1) was identified from the human liver cytosol as an enzyme decreasing MFA-quinoneimine formation. Addition of recombinant SOD1 into the reaction mixture decreased the formation of MFA-quinoneimine from MFA by recombinant CYP1A2. By a structure-activity relationship study, we found that SOD1 decreased the formation of quinoneimines from flufenamic acid and tolfenamic acid, but did not affect those produced from acetaminophen, amodiaquine, diclofenac, and lapatinib. Thus, SOD1 may selectively decrease the quinoneimine formation from fenamate-class NSAIDs. To examine whether SOD1 can attenuate cytotoxicity caused by MFA, siRNA for SOD1 was transfected into CYP1A2-overexpressed HepG2 cells. The leakage of lactate dehydrogenase caused by MFA treatment was significantly increased by knockdown of SOD1. In conclusion, we found that SOD1 can serve as a detoxification enzyme for quinoneimines to protect from drug-induced toxicity.