Estradiol and progesterone modulate halothane-induced liver injury in mice

Toyoda, Yasuyuki; Miyashita, Taishi; Endo, Shinya; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.toxlet.2011.03.031

Cited by 37 publications

(27 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An immune‐mediated DILI model showed sex differences in immune response and inflammation: more severe hepatitis, more antibody production, and a higher level of pro‐inflammatory hepatic cytokines in females vs. male mice . In the halothane‐induced liver injury mouse model, oestrogens reduce injury while progesterone exacerbates injury . In an immune‐mediated nephritis model more apoptosis occurred in females vs. more necrosis in males, and the administration of oestrogen to male mice induced apoptosis and inhibited necrosis .…”

Section: Introductionmentioning

confidence: 99%

“…8 In the halothane-induced liver injury mouse model, oestrogens reduce injury while progesterone exacerbates injury. 9,10 In an immune-mediated nephritis model more apoptosis occurred in females vs. more necrosis in males, and the administration of oestrogen to male mice induced apoptosis and inhibited necrosis. 11 Taken together, these findings suggest that gender and sex hormones may modulate host responses to liver injury insults and contribute to diverse clinical manifestation and severity of human DILI.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Associations of gender and a proxy of female menopausal status with histological features of drug‐induced liver injury

Suzuki

Barnhart

et al. 2017

Liver International

View full text Add to dashboard Cite

Background and aim Gender and menopause may contribute to type and severity of drug-induced liver injury (DILI) by influencing host responses to injury. The aim of this study was to assess the associations of gender and female age 50 [a proxy of menopause] with histologic features of liver injury in 212 adults enrolled in the Drug-Induced Liver Injury Network (DILIN) registry. Methods All participants had a causality score of at least ‘probable’, a liver biopsy within 30 days of DILI onset, and no prior chronic liver disease. Biochemical and histologic injury types were classified as hepatocellular or cholestatic/mixed injury. The cohort was divided into three gender/age categories: men (41.0%), women < 50 years (27.4%), and women ≥ 50 years of age (31.6%). Interaction of gender and age category (≥50 or not) was assessed. Results Hepatocellular injury was more prevalent in women < 50 years vs. others (p=0.002). After adjusting for biochemical injury types, black race and possible aging effects, more severe interface hepatitis was noted in biopsies of women < 50 years compared to those of men and women ≥ 50 years (p=0.009 and p=0.055, respectively). Compared to those of men, biopsies of women showed greater plasma cell infiltration, hepatocyte apoptosis, hepatocyte rosettes, and lobular disarray but less iron-positive hepatocytes and histological cholestasis (p<0.05). These associations persisted after excluding cases of amoxicillin/clavulanic acid, anabolic steroids or nitrofurantoin DILI which showed gender-specific distributions. Conclusion Gender and a proxy of menopause were associated with various features of inflammation and injury in DILI.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Associations of gender and a proxy of female menopausal status with histological features of drug‐induced liver injury

Suzuki

Barnhart

et al. 2017

Liver International

View full text Add to dashboard Cite

show abstract

“…Little is known about the possible mechanisms by which progesterone exerts its effects on b-cells; however, studies have shown that this hormone is able to modulate the generation of reactive oxygen species (ROS) and oxidative stress in different cell types (Nguyen & Syed 2011, Toyoda et al 2011. Thus, as the pancreatic b-cells present very low activities of antioxidant enzymes (Tiedge et al 1997) and it has been observed that the overexpression of these enzymes protects these cells against diabetogenic insults (Lortz et al 2000, Azevedo-Martins et al 2003, Gurgul et al 2004, we considered that progesterone might act through an oxidative-stressdependent mechanism that has been recognised as a stimulus for endoplasmic reticulum (ER) stress and for the unfolded protein response (UPR) (Cao & Kaufman 2012).…”

Section: Introductionmentioning

confidence: 99%

Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism

Nunes¹,

Portioli-Sanches²,

Rosim³

et al. 2014

Journal of Endocrinology

View full text Add to dashboard Cite

Progesterone has been associated with the development of gestational diabetes (GD) due to the enhancement of insulin resistance. As b-cell apoptosis participates in type 1 and type 2 diabetes pathophysiology, we proposed the hypothesis that progesterone might contribute to the development of GD through a mechanism that also involves b-cell death. To address this question, RINm5F insulin-producing cells were incubated with progesterone (25-100 mM), in the presence or absence of a-tocopherol (40 mM). After 24 or 48 h, membrane integrity and DNA fragmentation were analyzed by flow cytometry. Caspase activity was used to identify the mode of cell death. The involvement of endoplasmic reticulum stress in the action of progesterone was investigated by western blotting. Oxidative stress was measured by 2',7'-dichlorofluorescein diacetate (DCFDA) oxidation. Isolated rat islets were used in similar experiments in order to confirm the effect of progesterone in primary b-cells. Incubation of RINm5F cells with progesterone increased the number of cells with loss of membrane integrity and DNA fragmentation. Progesterone induced generation of reactive species. Pre-incubation with a-tocopherol attenuated progesterone-induced apoptosis. Western blot analyses revealed increased expression of CREB2 and CHOP in progesteronetreated cells. Progesterone caused apoptotic death of rat islet cells and enhanced generation of reactive species. Our results show that progesterone can be toxic to pancreatic b-cells through an oxidative-stress-dependent mechanism that induces apoptosis. This effect may contribute to the development of GD during pregnancy, particularly under conditions that require administration of pharmacological doses of this hormone.

show abstract

“…A recent study described how estrogen reduces hepatotoxicity after intraperitoneal exposure to halothane, but the roles of sex steroids in the autoimmune type of this disease have not been investigated [10]. Many autoimmune diseases preferentially affect women.…”

Section: Introductionmentioning

confidence: 99%

Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6

Cho

Kim

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Background and AimsImmune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI.MethodsTo model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function.ResultsBALB/c females developed more severe hepatitis (p<0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001) and females (p<0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01) and higher IL-1β (p<0.01) and IL-6 (p<0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05) suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6.Conclusions17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a therapeutic approach to DILI.

show abstract

Estradiol and progesterone modulate halothane-induced liver injury in mice

Cited by 37 publications

References 40 publications

Associations of gender and a proxy of female menopausal status with histological features of drug‐induced liver injury

Associations of gender and a proxy of female menopausal status with histological features of drug‐induced liver injury

Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism

Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6

Contact Info

Product

Resources

About