Altered gene expression in the liver of gamma-glutamyl transpeptidase-deficient mice.
We used mice deficient in gamma-glutamyl transpeptidase (GGT) to analyze the effects of GGT deficiency and altered thiol levels on gene expression in liver. GGT-deficient mice have markedly reduced levels of glutathione (GSH), cysteine, methionine, and cysteinylglycine in liver. Steady-state RNA levels of the catalytic subunit of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in GSH synthesis, are elevated 4-fold in these mice, while those for glutathione synthetase (GSH syn) are elevated 2-fold. RNA levels of cystathionase (cystathionine gamma-lyase), a key enzyme in the synthesis of cysteine from methionine, are elevated approximately 3.5-fold. In contrast, levels of RNA coding for multidrug resistance protein 2 (MRP2), which transports GSH into bile, are half wild-type values. We found no change in RNA levels of enzymes related to oxidative injury (CuZn and Mn superoxide dismutases [SOD], catalase, and glutathione peroxidase). Similarly, RNA levels of glutathione reductase and ribonucleotide reductase were unchanged. Furthermore, in contrast to previous in vitro results, methyl methanesulfonate did not induce stress-activated signal transduction as measured by c-jun phosphorylation in livers of GGT-deficient mice, despite further depletion of GSH by buthionine sulfoximine. Our findings indicate that GGT deficiency itself and/or altered thiol levels regulate expression of genes involved in GSH metabolism, but have no effect on the expression of other antioxidant genes.
Habib
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Department of Pathology, Baylor College of Medicine, Houston TX 77030, USA.
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Lieberman
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D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000235:genetics; D004798:Enzymes / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000172:deficiency*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D004798:Enzymes; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; C095122:multidrug resistance protein 3; D010088:Oxidoreductases; D005723:gamma-Glutamyltransferase; D003542:Cystathionine gamma-Lyase; D005978:Glutathione