title: Estradiol and progesterone modulate halothane-induced liver injury in mice.
abstract: Drug-induced liver injury (DILI) is one of the major problems in drug development and clinical drug therapy. In general, it is believed that women exhibit worse outcomes from DILI than men. It is known that halothane (HAL), an inhaled anesthetic, rarely induces severe liver injury. The risk factors for severe HAL-induced liver injury (HILI) are female sex, genetics and adult age. To investigate the underlying mechanism by which women are more susceptible to HILI, we focused on two major female sex hormones, estradiol (E2) and progesterone (Prog). In this study, we first found that pretreatment of mice with E2 attenuated HILI, whereas pretreatment with Prog exacerbated HILI. E2 and Prog had no effects on the degree of metabolic activation, the ratio of GSH/GSSG or oxidative stress in the liver. We observed higher numbers of neutrophils infiltrated into the liver and increased hepatic mRNA levels of proinflammatory cytokines, tumor necrosis factor (TNF) α, interleukin (IL)-1β and IL-6 and chemokines, CXCL1 and CXCL2 by pretreatment with Prog, whereas E2 pretreatment resulted in the opposite effects. These results suggest that E2 and Prog play a critical role in HILI via immune-related responses and female sex hormone balance might represent a risk factor for HILI.
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: Taishi
authors.initials: T
authors.lastname: Miyashita
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
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; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000032:analysis; D054426:Chemokine CXCL2 / Q000032:analysis; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006221:Halothane / Q000009:adverse effects*; D020381:Interleukin-17 / Q000032:analysis; D053583:Interleukin-1beta / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D004958:Estradiol; D005978:Glutathione; D006221:Halothane