(A) Scheme of selected biochemical reactions and metabolites involved in GSH metabolism (via γ-glutamyl cycle) and trans-methylation and trans-sulfuration pathways. Solid lines with arrow indicate single biochemical reactions. Solid lines terminated by solid diamond indicates cellular source. Hepatic concentrations of (B) GSH and GSSG, (C) glutamate and threonine, and (D) SAM and SAH. Results are expressed in mole per gram (g) liver weight. Data are presented as floating bars (min to max, line at mean; N = 4/group) showing individual data points from wild-type (WT, closed circles) and Gclm-KO (KO, open circles) mice. *P < 0.05, **P < 0.01, ***P < 0.001 by two-way ANOVA with post-hoc Holm-Sidak's multiple comparisons test. (E) Relative mRNA abundance measured by Q-PCR. Results are expressed as mean ± S.D. (N = 4/group). *Compared to WT-CON, ^compared to WT-EtOH, or #compared to KO-CON: P < 0.05 by two-way ANOVA with post-hoc Holm-Sidak's multiple comparisons test. WT-CON, wild-type mice fed control diet; KO-CON, Glcm KO mice fed control diet; WT-EtOH, wild-type mice fed ethanol-containing diet; KO-EtOH, Glcm KO mice fed ethanol-containing diet. Cys, cysteine; γ-GC, γ-glutamylcysteine; Gln, glutamine; Glu, glutamate; Gly, glycine; Hcy, homocysteine; Met, methionine; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; GCL, glutamate-cysteine ligase; GCLC, catalytic subunit of GCL; GCLM, modifier subunit of GCL; GLS, glutaminase; GLUD, glutamate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; GPX, glutathione peroxidase; GSR, glutathione disulfide reductase; GST, glutathione S-transferase.