title: Mechanism of exacerbative effect of progesterone on drug-induced liver injury.
abstract: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is generally believed that women exhibit worse outcomes from DILI than men. Recently, we found that pretreatment of mice with estradiol attenuated halothane (HAL)-induced liver injury, whereas pretreatment with progesterone exacerbated it in female mice. To investigate the mechanism of sex difference of DILI, we focused on progesterone in this study. We found the exacerbating effect of progesterone in thioacetamide (TA), α-naphthylisothiocyanate, and dicloxacillin-induced liver injury only in female mice. Higher number of myeloperoxidase-positive mononuclear cells infiltrated into the liver and increased levels of Chemokine (C-X-C motif) ligand 1 and 2 (CXCL1 and CXCL2) and intercellular adhesion molecule-1 in the liver were observed. Interestingly, CXCL1 was slightly increased by progesterone pretreatment alone. Progesterone pretreatment increased the extracellular signal-regulated kinase (ERK) phosphorylation in HAL-induced liver injury. Pretreatment with U0126 (ERK inhibitor) significantly suppressed the exacerbating effect of progesterone and the expression of inflammatory mediators. In addition, pretreatment with gadolinium chloride (GdCl(3): inhibitor of Kupffer cells) significantly suppressed the exacerbating effect of progesterone pretreatment and the expression of inflammatory mediators. Moreover, posttreatment of RU486 (progesterone receptor antagonist) 1 h after the HAL or TA administration ameliorated the HAL- or TA-induced liver injury, respectively, in female mice. In conclusion, progesterone exacerbated the immune-mediated hepatotoxic responses in DILI via Kupffer cells and ERK pathway. The inhibition of progesterone receptor and decrease of the immune response may have important therapeutic implications in DILI.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Taishi
authors.initials: T
authors.lastname: Miyashita
authors.forename: Azusa
authors.initials: A
authors.lastname: Yano
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D011374:Progesterone