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Exp Biol Med (Maywood). 2013 Apr;238(4):360-9. doi: 10.1177/1535370213477987.

Acute glutathione depletion induces hepatic methylglyoxal accumulation by impairing its detoxification to D-lactate.

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Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.


Methylglyoxal (MGO) is a dicarbonyl that reacts with amino acids and nucleic acids to form advanced glycation endproducts, which may contribute to diabetes and its cardiovascular complications. MGO detoxification through the glyoxalase (GLO) pathway is glutathione (GSH)-dependent, but no studies have investigated whether acute depletion of GSH regulates MGO accumulation in vivo. We therefore administered a single intraperitoneal injection of the specific GSH biosynthesis inhibitor l-buthionine-(RS)-sulfoximine (BSO; 4 mmol/kg) or phosphate-buffered saline vehicle to six-week-old Sprague Dawley rats (n = 48) prior to sacrificing at 0, 6, 12 and 48 h (n = 6/time point/treatment). BSO had no effect (P > 0.05) on adipose or plasma MGO at any specific time points following treatment. In contrast, hepatic GSH was 68-71% lower (P < 0.05) at 6-12 h following BSO, and MGO was 27% higher at 12 h. At 12 h, hepatic d-lactate was 13% lower and GLO activity was 52% lower following BSO, which was fully restored by the exogenous addition of GSH. Hepatic GSH was inversely related to hepatic MGO (r = -0.81; P < 0.01) and positively correlated with hepatic GLO activity (r = 0.72; P < 0.01), whereas hepatic GLO activity was positively correlated with hepatic d-lactate (r = 0.63; P < 0.05). BSO had no effect on hepatic malondialdehyde or vitamin E. These findings demonstrate that GSH depletion in vivo increases hepatic MGO accumulation by impairing its GSH-dependent, GLO-mediated detoxification to d-lactate independent of oxidative stress.


S -d-lactoylglutathione; buthionine sulfoximine; glutathione; glyoxalase I; glyoxalase II; pyruvaldehyde

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