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Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?

ABSTRACT: There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex differences relevant to humans. To date, male and female human hepatocytes have not yet been compared in terms of their responses to hepatotoxic drugs. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for certain parameters and individual drugs, showing an overall higher sensitivity of female primary hepatocytes to hepatotoxicants. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.

SUBMITTER: Mennecozzi M

PROVIDER: S-EPMC4388670 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?

Mennecozzi Milena M Landesmann Brigitte B Palosaari Taina T Harris Georgina G Whelan Maurice M

PloS one 20150407 4

There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex d ...[more]

PMID: 25849576

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Project description:ImportanceStudies have found that female surgeons have fewer opportunities to perform highly remunerated operations, a circumstance that contributes to the sex-based pay gap in surgery. Procedures performed by surgeons are, in part, determined by the referrals they receive. In the US and Canada, most practicing physicians who provide referrals are men. Whether there are sex-based differences in surgical referrals is unknown.ObjectiveTo examine whether physicians' referrals to surgeons are influenced by the sex of the referring physician and/or surgeon.Design, setting, and participantsThis cross-sectional, population-based study used administrative databases to identify outpatient referrals to surgeons in Ontario, Canada, from January 1, 1997, to December 31, 2016, with follow-up to December 31, 2018. Data analysis was performed from April 7, 2019, to May 14, 2021.ExposuresReferring physician sex.Main outcomes and measuresThis study compared the proportion of referrals (overall and those referrals that led to surgery) made by male and female physicians to male and female surgeons to assess associations between surgeon, referring physician, or patient characteristics and referral decisions. Discrete choice modeling was used to examine the extent to which sex differences in referrals were associated with physicians' preferences for same-sex surgeons.ResultsA total of 39 710 784 referrals were made by 44 893 physicians (27 792 [61.9%] male) to 5660 surgeons (4389 [77.5%] male). Female patients made up a greater proportion of referrals to female surgeons than to male surgeons (76.8% vs 55.3%, P < .001). Male surgeons accounted for 77.5% of all surgeons but received 87.1% of referrals from male physicians and 79.3% of referrals from female physicians. Female surgeons less commonly received procedural referrals than male surgeons (25.4% vs 33.0%, P < .001). After adjusting for patient and referring physician characteristics, male physicians referred a greater proportion of patients to male surgeons than did female physicians; differences were greatest among referrals from other surgeons (rate ratio, 1.14; 95% CI, 1.13-1.16). Female physicians had a 1.6% (95% CI, 1.4%-1.9%) greater odds of same-sex referrals, whereas male physicians had a 32.0% (95% CI, 31.8%-32.2%) greater odds of same-sex referrals; differences did not attenuate over time.Conclusions and relevanceIn this cross-sectional, population-based study, male physicians appeared to have referral preferences for male surgeons; this disparity is not narrowing over time or as more women enter surgery. Such preferences lead to lower volumes of and fewer operative referrals to female surgeons and are associated with sex-based inequities in medicine.

Project description:1. Glutathione peroxidase activity in the livers of sham-operated female rats was about 60% higher than in similarly treated male rats. The value in the ovariectomized female was about the same as that in the castrated or sham-operated male. 2. Glutathione peroxidase activity changed during the oestrous cycle. The highest value was in oestrus, and was about 50% higher than the lowest activity, which was found in dioestrus. The activity in proestrus and in metoestrus was respectively about 20 and 30% higher than in dioestrus. 3. In the pregnant female 1 or 2 days before term, glutathione peroxidase activity was about 20% higher than that in the female in oestrus. 4. Subcutaneous implants of both oestra-diol and progesterone in the gonadectomized rats increased the glutathione peroxidase activity approximately to the values found in the female at oestrus. 5. The rate of aerobic oxidation of GSH in the female rat liver was about 80% higher than in the male and about 110% higher than in the gonadectomized rats. Treatment of gonadectomized rats with subcutaneous implants of oestradiol and of progesterone increased the rate of oxidation of GSH by about 100%. 6. In the presence of azide the rate of GSH oxidation in the male and in the female was respectively about 3.5- and 2.1-fold that in the absence of azide. In castrated or ovariectomized rats the increase due to the presence of azide was about 2.4-fold. In the gonadectomized rats treated with oestradiol or progesterone the rate of GSH oxidation in the presence of azide was about 2.2-fold that in its absence. 7. The rate of lipid peroxidation in female was 15-30-fold that in male or in gonadectomized rats. Treatment of the gonadectomized rats with oestradiol or with progesterone increased the rate of lipid peroxidation up to values that were even higher than in the female. In the presence of GSH the formation of malonaldehyde from peroxides was virtually eliminated. 8. The results suggest that the sex-linked differences in glutathione peroxidase activity, in the rate of GSH oxidation and in the rate of lipid peroxidation are due to the female sex hormones. 9. It is suggested that both the catalase activity and the rate of hydrogen peroxide formation are higher in the male than in the female. 10. Sex-linked changes in glutathione peroxidase, in the rate of GSH oxidation and in the rate of lipid peroxide formation are discussed in relation to the metabolism of oestrogens in the liver and also to the possible nature of those sex-linked changes.

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Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?

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Sex differences in liver toxicity-do female and male human primary hepatocytes react differently to toxicants in vitro?

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