title: Involvement of protoporphyrin IX accumulation in the pathogenesis of isoniazid/rifampicin-induced liver injury: the prevention of curcumin.
abstract: Combination of isoniazid (INH) and rifampicin (RFP) causes liver injury frequently among tuberculosis patients. However, mechanisms of the hepatotoxicity are not entirely understood. Protoporphyrin IX (PPIX) accumulation, as an endogenous hepatotoxin, resulting from isoniazid and rifampicin co-therapy (INH/RFP) has been reported in PXR-humanized mice. Aminolevulinic acid synthase1 (ALAS1), ferrochelatase (FECH) and breast cancer resistance protein (BCRP) play crucial roles in PPIX synthesis, metabolism and transport, respectively. Herein, this study focused on the role of INH/RFP in these processes. We observed PPIX accumulation in human hepatocytes (L-02) and mouse livers. FECH expression was initially found downregulated both in L-02 cells and mouse livers and expression levels of ALAS1 and BCRP were elevated in L-02 cells after INH/RFP treatment, indicating FECH inhibition and ALAS1 induction might confer a synergistic effect on PPIX accumulation. Additionally, our results revealed that curcumin alleviated INH/RFP-induced liver injury, declined PPIX levels and induced FECH expression in both L-02 cells and mice. In conclusion, our data provide a novel insight in the mechanism of INH/RFP-induced PPIX accumulation and evidence for understanding pathogenesis of INH/RFP-induced liver injury, and suggest that amelioration of PPIX accumulation might be involved in the protective effect of curcumin on INH/RFP-induced liver injury.
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.|b School of Pharmaceutical Sciences, Central South University , Changsha , China.
authors.forename: Leiyan
authors.initials: L
authors.lastname: He
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.|b School of Pharmaceutical Sciences, Central South University , Changsha , China.
authors.forename: Yaoxue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.|b School of Pharmaceutical Sciences, Central South University , Changsha , China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Deng
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.|b School of Pharmaceutical Sciences, Central South University , Changsha , China.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.
authors.forename: Chengzi
authors.initials: C
authors.lastname: Zuo
authors.affiliation: a Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Central South University , Changsha , China and.
authors.forename: Wenxing
authors.initials: W
authors.lastname: Peng
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D003474:Curcumin / Q000494:pharmacology*; D007538:Isoniazid / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D051379:Mice; D017319:Photosensitizing Agents; D011524:Protoporphyrins / Q000494:pharmacology*; D012293:Rifampin / Q000633:toxicity; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000995:Antitubercular Agents; D017319:Photosensitizing Agents; D011524:Protoporphyrins; C028025:protoporphyrin IX; D003474:Curcumin; D007538:Isoniazid; D012293:Rifampin
keywords: Antitubercular drugs; curcumin; drug-induced liver injury; heme precursor; hepatotoxicity; isoniazid; protoporphyrin IX; rifampicin