ABSTRACT
Title
Glutamyl cycle in the rat liver appears to be sex-gender specific
Authors
I. Campesi1,2,3, A. Galistu A1,3, C. Carru 4, F. Franconi 1,2,3, A. Zinellu 4,5
1 Department of Pharmacology, University of Sassari,
2 National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy
3 Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
4 Dept. Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
5 Porto Conte Ricerche Srl, Tramariglio, Alghero, Sassari, Italy
1 Department of Pharmacology, University of Sassari,
2 National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy
3 Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
4 Dept. Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari
5 Porto Conte Ricerche Srl, Tramariglio, Alghero, Sassari, Italy
Abstract
Several studies supported the existence of sexual dimorphism in the liver. Female, in fact, are more susceptible than male to drug and xenobiotic-induced hepatotoxicity even if the bases of these differences are not well known. A primary role in detoxification processes is played by GSH. GSH biosynthesis depends on several factors including glutamylcysteine ligase (GCL)activity which is physiologically regulatedby: a) the availability of L-cysteine; b) non-allosteric feedback competitive inhibition by GSH; c) aging, a condition associated with a decrease in GSH and GCL mRNA levels, especially in males; d) hormones such as cortisteroids, insulin and exogenous estrogens that increase GCL expression and GSH levels in livers of both male and female mice; e) lipid peroxidation products that may contribute to the rapid activation of GCL. For most cells, the glutamyl cycle allows GSH to be used as a continuous source of L-cysteine, an important function because L-cysteine can auto-oxidize to cystine, thus reducing potentially toxic oxygen free radicals.
Because the underlying biological mechanisms of the greater sensitivity of females to chemical-induced liver injury are unknown, we decided to investigate sex-gender differences related to the biosynthesis and metabolism of GSHin the rat liver.
While the liver of young male and female rats do not differ in levels of Lmethionine, glutathione, taurine and malondialdehyde, (a proxy of lipid peroxidation), female rat livers have a significantly higher level of L-cysteine than male rat livers. The female liver expresses less GCL, the key enzyme in glutathione synthesis, than the male rat liver. Finally, there is a positive correlation between L-methionine and L-cysteine and between L-cysteine and glutathione in male but not in female livers.
These data suggest that the glutamyl cycle in the liver is sexually dimorphic and thatsex-gender differences in the metabolism and biosynthesis of sulphur compounds could have important consequences for liver function and the understanding of drug and xenobiotic hepatotoxicty which appears to be sex-gender specific.
Because the underlying biological mechanisms of the greater sensitivity of females to chemical-induced liver injury are unknown, we decided to investigate sex-gender differences related to the biosynthesis and metabolism of GSHin the rat liver.
While the liver of young male and female rats do not differ in levels of Lmethionine, glutathione, taurine and malondialdehyde, (a proxy of lipid peroxidation), female rat livers have a significantly higher level of L-cysteine than male rat livers. The female liver expresses less GCL, the key enzyme in glutathione synthesis, than the male rat liver. Finally, there is a positive correlation between L-methionine and L-cysteine and between L-cysteine and glutathione in male but not in female livers.
These data suggest that the glutamyl cycle in the liver is sexually dimorphic and thatsex-gender differences in the metabolism and biosynthesis of sulphur compounds could have important consequences for liver function and the understanding of drug and xenobiotic hepatotoxicty which appears to be sex-gender specific.