Sex differences in glutathione metabolism and acetaminophen toxicity

Abstract

Aims: Clinical and experimental evidence has shown that females in humans and other mammals have higher glutathione (GSH) levels than males, which are caused by higher levels of estradiol. Understanding how hepatic GSH level and synthesis velocity depend on the sex hormones is an extremely important question since oxidative stress contributes to the risk for heart disease and cancer, and oxidative stress is reduced by GSH. Our aim is to develop a systems approach to understanding GSH metabolism and use this to explain the causes of GSH differences in males and females, how GSH changes during the menstrual cycle, and why women may be less susceptible to acetaminophen toxicity.

Methods: We use mathematical models for hepatic glutathione metabolism, including one-carbon metabolism and acetaminophen detoxification, to investigate how the activation of certain enzymes by estradiol leads to dramatic changes in reaction velocities and metabolite concentrations.

Results: The models explain why women of childbearing age have higher glutathione than men, and that this is caused by the balance of activation of glutamyl cysteine synthetase (GCL) and glutathione peroxidase (GPX) by estradiol. The steady-state concentration of glutathione in women depends on the strength of the activation of GCL and GPX and is quite homeostatic over a wide range of activations.

Conclusions: During the menstrual cycle, the GSH concentration changes daily but over a relatively narrow range. We explain how this dynamic homeostasis depends on the biochemical network that produces GSH. The model is also consistent with published results that show that female mice are less susceptible than males to hepatotoxicity due to acetaminophen overdose and suggests that this might also be true for humans, though the human epidemiological data are contradictory.

Keywords

Sex differences / glutathione / metabolism / liver / acetaminophen toxicity

References

[1] Bellanti F,Rollo T.Sex hormones modulate circulating antioxidant enzymes: impact of estrogen therapy.Redox Biol2013;1:340-6 PMCID:PMC3757703

[2] Abbas AM.Effects of 17β-estradiol and antioxidant administration on oxidative stress and insulin resistance in ovariectomized rats.Can J Physiol Pharmacol2011;89:497-504

[3] Borrás C,García-Sala D,Pallardó FV.Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males.Free Radic Biol Med2003;34:546-52

[4] Martínez de Toda I,Díaz-Del Cerro E,Carracedo J.Sex differences in markers of oxidation and inflammation. Implications for ageing.Mech Ageing Dev2023;211:111797

[5] Dabrosin C.Variability of glutathione during the menstrual cycle-due to estrogen effects on hepatocytes?.Free Radic Biol Med2004;36:145-51

[6] Ha EJ.Plasma selenium and plasma and erythrocyte glutathione peroxidase activity increase with estrogen during the menstrual cycle.J Am Coll Nutr2003;22:43-51

[7] Wang L,Asmis R.Sexual dimorphism in glutathione metabolism and glutathione-dependent responses.Redox Biol2020;31:101410 PMCID:PMC7212491

[8] Salonen JT,Huttunen JK,Puska P.Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study.Lancet1982;2:175-9

[9] Combs GF Jr.Chemopreventive agents: selenium.Pharmacol Ther1998;79:179-92

[10] Ben-Shachar R,Luo S,Reed M.The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model.Theor Biol Med Model2012;9:55 PMCID:PMC3576299

[11] Kim R,Reed MC.One-carbon metabolism during the menstrual cycle and pregnancy.PLoS Comput Biol2021;17:e1009708 PMCID:PMC8741061

[12] Nijhout HF,Anderson DF,James SJ.Long-range allosteric interactions between the folate and methionine cycles stabilize DNA methylation reaction rate.Epigenetics2006;1:81-7

[13] Nijhout HF,Budu P.A mathematical model of the folate cycle: new insights into folate homeostasis.J Biol Chem2004;279:55008-16

[14] Reed MC,Pavisic J,Ulrich CM.A mathematical model of glutathione metabolism.Theor Biol Med Model2008;5:8 PMCID:PMC2391141

[15] Reed MC,Nijhout HF.The biological significance of substrate inhibition: a mechanism with diverse functions.Bioessays2010;32:422-9.

[16] Thanacoody H,Reed M. Mathematical modelling of the effect of a high dose acetylcysteine regimen based on the SNAP trial on hepatic glutathione regeneration and hepatocyte death. Available from: https://www.tandfonline.com/doi/epdf/10.3109/15563650.2016.1165952?needAccess=true [Last accessed on 8 Apr 2024]

[17] McConnachie LA,Hudson FN.Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice.Toxicol Sci2007;99:628-36

[18] Du K,McGill MR.Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.Toxicol Appl Pharmacol2014;281:58-66 PMCID:PMC4362889

[19] Björnsson ES,Björnsson HK,Olafsson S.Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology2013;144:1419-25, 1425.e1-3; quiz e19-20

[20] Rubin J,Gottfried M,Sarkar M.Sex differences in acetaminophen-induced acute liver injury and acute liver failure.J Hepatol2016;64:S173-4

[21] Marzilawati AR,Mahadeva S.Low rates of hepatotoxicity among Asian patients with paracetamol overdose: a review of 1024 cases.BMC Pharmacol Toxicol2012;13:8 PMCID:PMC3517419

[22] Sadre-Marandi F,Reed MC.Sex differences in hepatic one-carbon metabolism.BMC Syst Biol2018;12:89 PMCID:PMC6201565

[23] Pinto RE.The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates.Biochem J1969;112:109-15 PMCID:PMC1187646

[24] Sluss PM,Adams JM.Mass spectrometric and physiological validation of a sensitive, automated, direct immunoassay for serum estradiol using the architect.Clin Chim Acta2008;388:99-105

[25] Stricker R,Chevailler MC,Bischof P.Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer.Clin Chem Lab Med2006;44:883-7

[26] Cooke PS,Ko C,Hess RA.Estrogens in male physiology.Physiol Rev2017;97:995-1043 PMCID:PMC6151497

[27] Inoue M,Tran T.Glutathione transport across hepatocyte plasma membranes. Analysis using isolated rat-liver sinusoidal-membrane vesicles.Eur J Biochem1984;138:491-5

[28] Wu G,Turner ND,Yang S.Glutathione metabolism and its implications for health.J Nutr2004;134:489-92

[29] Griffith OW.Biologic and pharmacologic regulation of mammalian glutathione synthesis.Free Radic Biol Med1999;27:922-35

[30] James SJ,Melnyk S.Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.Am J Clin Nutr2004;80:1611-7

[31] Pogribna M,Pogribny I,Yi P.Homocysteine metabolism in children with Down syndrome: in vitro modulation.Am J Hum Genet2001;69:88-95 PMCID:PMC1226051

[32] Daly FF,Murray L,Buckley NA.Panel of Australian and New Zealand clinical toxicologistsGuidelines for the management of paracetamol poisoning in Australia and New Zealand--explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres.Med J Aust2008;188:296-301

[33] Lee WM.Acetaminophen-related acute liver failure in the United States.Hepatol Res2008;38 Suppl 1:S3-8

[34] Prescott LF.Kinetics and metabolism of paracetamol and phenacetin.Br J Clin Pharmacol1980;10 Suppl 2:291S-8S PMCID:PMC1430174

[35] Masubuchi Y,Watanabe Y.Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine.Toxicology2011;287:54-60

[36] Ramachandran A.Mitochondria in acetaminophen-induced liver injury and recovery: a concise review.Livers2023;3:219-31 PMCID:PMC10299745

[37] Nguyen NT,Smith S.Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice.Arch Toxicol2023;97:1397-412 PMCID:PMC10680445

[38] Remien CH,Waddoups L,Sussman NL.Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death.Hepatology2012;56:727-34

[39] Schilling A,Leonard M.Acetaminophen: old drug, new warnings.Cleve Clin J Med2010;77:19-27.

[40] Prescott LF,Critchley JA,Adam RD.Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning.Br Med J1979;2:1097-100 PMCID:PMC1597048

[41] Smilkstein MJ,Kulig KW.Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985).N Engl J Med1988;319:1557-62

[42] Link SL,Osmon S,Rumack BH.Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series..Clin Toxicol2022;60:472-7

[43] Dart RC,Matoushek T.Management of acetaminophen poisoning in the US and Canada: a consensus statement.JAMA Netw Open2023;6:e2327739

[44] Boeuf S,Franssen-Van Hal NL.Individual variation of adipose gene expression and identification of covariated genes by cDNA microarrays.Physiol Genomics2002;11:31-6

[45] Oleksiak MF,Crawford DL.Variation in gene expression within and among natural populations.Nat Genet2002;32:261-6

[46] Sigal A,Cohen A.Variability and memory of protein levels in human cells.Nature2006;444:643-6.

[47] Itagaki T,Cheng X.Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells.Gut2005;54:1782-9 PMCID:PMC1774809

[48] Yuan XH,Yang CR.Progesterone amplifies oxidative stress signal and promotes NO production via H₂O₂ in mouse kidney arterial endothelial cells.J Steroid Biochem Mol Biol2016;155:104-11

[49] Ohwada M,Sato I,Watanabe K.Glutathione peroxidase activity in endometrium: effects of sex hormones and cancer.Gynecol Oncol1996;60:277-82