Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis

Abstract

Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.

Experimental models of metabolic and alcoholic fatty liver disease

“…CYP2E1, in particular, is implicated in the pathogenesis of both NAFLD and ALD in humans[ 5 , 27 ]. CYP2E1 metabolizes EtOH and other xenobiotics in a nicotinamide adenine dinucleotide phosphate (NADP + /NADPH)-mediated process and produces H 2 O 2 and O 2 – [ 28 ]. Mouse models also indicate that CYP2E1 plays a role in lipid dysregulation[ 29 ] and diabetes[ 30 ].…”

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication

“… 74 Ethanol tampers with the function of multiple enzymes, including MAT, BHMT, and various MTs. 76 , 77 Decreased MAT activity is attributable to alcohol-induced oxidative stress and reactive aldehydes, which can inactivate the liver-specific MAT. The lack of metabolic products due to impaired methionine metabolism inhibits remethylation of Hcy, the form of GSH, thus weakening defenses against oxidative stress.…”

“…The lack of PRMT causes lower PE methylation, which leads to SAM accumulation and sensitivity to oxidative stress. 73 , 74 , 76 – 78 , 81 – 83 Nonalcoholic fatty liver disease Hepatic Fgf21 mRNA was increased, which is a modulator of energy homeostasis. FFA accumulates and can cause lipotoxicity through JNK1 activation.…”

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

“…Acetaldehyde depletes GSH (glutathione) and hence intracellular redox eucrasia. Different mechanisms may participate: sequestering of GSH pools by non-enzymatic binding [72], reduction of GSH peroxidase (EC 1.11.1.9) activity [73], conjugation with GSH metabolites such as cysteinyl glycine [74,75], or disruption of the transsulfuration pathway [76]. However, in a murine experimental model of forced GSH depletion obtained by disrupting a glutamate-cysteine ligase modifier (GCLM) gene, Chen et al [77] showed that low levels of GSH protected liver tissue against the insult of ethanol by adapting the metabolic flux of several compounds to resist alcohol insult.…”

“…The term C1 metabolism refers to the circuitry of metabolic pathways (Figure 4) essential for cell proliferation and endurance (nucleotide synthesis, Ser Gly and Met metabolism, methylation reactions, synthesis of polyamines, redox reactions, and transsulfuration pathway) that manage the provision of one-carbon modules (methyl groups) and connects with the control of the cellular redox state [76,[112][113][114][115][116]. Folate (pteroil-L-glutamate) metabolism distributes one-carbon components through redox reactions.…”