Dr. Ron’s Research Review – November 11, 2015

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This week’s research review focuses on GGT.

Gamma-glutamyl transferase (transpeptidase, GGT) is an enzyme that transfers gamma-glutamyl functional groups.
GGT participates in the gamma-glutamyl cycle that recycles glutathione. GGT and dipeptidase (DP) break down glutathione into glycine and cysteine. (Lu, 2013)
GSH is a continuous source of cysteine, and GGT deficiency causes a deficiency of cysteine. (Lieberman et al., 1996)
Elevated GGT concentrations may be a clinical marker of depleted glutathione in alcoholic subjects. (Seifert and Anderson, 2007)

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Dr. Ron


 

Articles

Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice.
(Lieberman et al., 1996) Download
gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to approximately 20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the gamma-glutamyl cycle in cysteine and GSH homeostasis.

Glutathione synthesis.
(Lu, 2013) Download
BACKGROUND:  Glutathione (GSH) is present in all mammalian tissues as the most abundant non-protein thiol that defends against oxidative stress. GSH is also a key determinant of redox signaling, vital in detoxification of xenobiotics, and regulates cell proliferation, apoptosis, immune function, and fibrogenesis. Biosynthesis of GSH occurs in the cytosol in a tightly regulated manner. Key determinants of GSH synthesis are the availability of the sulfur amino acid precursor, cysteine, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The second enzyme of GSH synthesis is GSH synthetase (GS). SCOPE OF REVIEW:  This review summarizes key functions of GSH and focuses on factors that regulate the biosynthesis of GSH, including pathological conditions where GSH synthesis is dysregulated. MAJOR CONCLUSIONS:  GCL subunits and GS are regulated at multiple levels and often in a coordinated manner. Key transcription factors that regulate the expression of these genes include NF-E2 related factor 2 (Nrf2) via the antioxidant response element (ARE), AP-1, and nuclear factor kappa B (NFκB). There is increasing evidence that dysregulation of GSH synthesis contributes to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary and liver fibrosis, alcoholic liver disease, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. GENERAL SIGNIFICANCE:  GSH is a key antioxidant that also modulates diverse cellular processes. A better understanding of how its synthesis is regulated and dysregulated in disease states may lead to improvement in the treatment of these disorders. This article is part of a Special Issue entitled Cellular functions of glutathione.

Acetaminophen usage patterns and concentrations of glutathione and gamma-glutamyl transferase in alcoholic subjects.
(Seifert and Anderson, 2007) Download
STUDY OBJECTIVES:  To determine if subjects with chronic alcoholism are predisposed to acetaminophen-induced hepatotoxicity, and to determine the contributing factors. DESIGN:  Prospective cohort study. SETTING:  Community-based crisis intervention center. SUBJECTS:  One hundred eighty-eight subjects who answered "yes" to at least one of the four questions on the CAGE (Cut down-Annoyed-Guilty-Eye-opener) questionnaire for identifying alcoholism, and 10 healthy volunteers (controls). INTERVENTION:  A history, physical examination, urine toxicologic analysis, ethanol and drug therapy history, and venous blood samples were collected on all subjects. MEASUREMENTS AND MAIN RESULTS:  Venous blood was analyzed for a liver profile, prothrombin time, and total and oxidized glutathione concentrations. A significantly higher proportion of daily drinkers were regular daily users (29.2% [45/154] vs 11.8% [4/34], p=0.0497) as well as abusers (35.7% [55/154] vs 14.7% [5/34], p=0.0237) of acetaminophen compared with non daily drinkers. Alcoholic subjects with elevated gamma-glutamyl transferase (GGT >or= 51 U/L) levels had significantly lower median plasma glutathione concentrations (2.33 micromol/L, 95% confidence interval [CI] 1.74-2.69 micromol/L) compared with those of alcoholic subjects with normal GGT concentrations (5.97 micromol/L, 95% CI 4.39-7.03 micromol/L, p<0.0001) and healthy volunteers (6.59 micromol/L, 95% CI 4.79-9.65 micromol/L, p=0.0002). A significant inverse correlation was also noted between the GGT concentration and the plasma total glutathione concentration (r = -0.62, p<0.0001). None of the 188 subjects met all preset criteria for hepatotoxicity. CONCLUSIONS:  Daily drinkers were more than twice as likely as non daily drinkers to be regular daily acetaminophen users and abusers. Alcoholic subjects with elevated GGT concentrations had significantly lower plasma total glutathione concentrations, and plasma total glutathione concentrations inversely correlated with GGT concentrations. Elevated GGT concentrations may be a clinical marker of depleted glutathione in alcoholic subjects. Acetaminophen-induced hepatotoxicity appears to be uncommon in alcoholic subjects, despite the 31.9% (60/188 patients) who took doses that are potentially hepatotoxic.

References

Lieberman, MW, et al. (1996), ‘Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice.’, Proc Natl Acad Sci U S A, 93 (15), 7923-26. PubMedID: 8755578
Lu, SC (2013), ‘Glutathione synthesis.’, Biochim Biophys Acta, 1830 (5), 3143-53. PubMedID: 22995213
Seifert, CF and DC Anderson (2007), ‘Acetaminophen usage patterns and concentrations of glutathione and gamma-glutamyl transferase in alcoholic subjects.’, Pharmacotherapy, 27 (11), 1473-82. PubMedID: 17963456