Effects of chronic inhibition of glutathione biosynthesis on cholesterol and bile acid metabolism in rats.

The objective of this study was to examine the effect of chronic inhibition of glutathione (GSH) biosynthesis on cholesterol and bile acid metabolism in rats. Male Sprague-Dawley rats, weighing between 60 and 65 g, were randomly assigned to one of two groups and allowed a 1-week adaptation period to a 6 a.m.-6 p.m. light cycle. Food and water were available ad libitum. Following the adaptation period, 1 group was given a solution of 30 mM DL-buthionine sulfoximine (BSO, an inhibitor of GSH biosynthesis) in saline, while the other group received saline only. All studies were carried out during, or at the end of the second week of BSO treatment. While body weight was minimally affected by BSO treatment, liver weight (% of body weight) was significantly greater in the BSO group (control 4.8 +/- 0.2 vs. BSO 5.2 +/- 0.3; P less than 0.05). The increase in liver weight, however, was not associated with a change in the specific content of cytochrome P-450. Even though fecal output (g/100 g per day) was significantly greater in the BSO group (control 2.4 +/- 0.1 vs. BSO 2.7 +/- 0.3; P less than 0.05), it was not commensurate with an increase in fecal bile acids and neutral sterols. In fact, fecal bile acid excretion (mg/100 g per day) was significantly reduced in the BSO group (control 9.0 +/- 2.0 vs. BSO 6.2 +/- 0.9; P less than 0.05), a finding consistent with a significant reduction in bile acid pool size (mg/100 g) in that group (control 23.1 +/- 1.9 vs. BSO 14.3 +/- 4.8; P less than 0.05). Hepatic GSH content (mumol/g) and cholesterol 7 alpha-hydroxylase activity (pmol/mg per min) were assayed at two time points: 12-2 a.m. (mid-dark point) and 12-2 p.m. (mid-light point). At mid-dark point, BSO-treated animals had a significantly lower hepatic GSH content (control 4.5 +/- 0.3 vs. BSO 0.6 +/- 0.3; P less than 0.05) and a significantly lower cholesterol 7 alpha-hydroxylase activity (control 33.5 +/- 1.3 vs. BSO 14.7 +/- 3.9; P less than 0.05). At mid-light point, hepatic GSH content in the two groups was similar to that at mid-dark point. While cholesterol 7 alpha-hydroxylase activity in both groups was significantly lower (P less than 0.05) at mid-light point relative to that at mid-dark point, there was no difference between the two groups in cholesterol 7 alpha-hydroxylase activity at mid-light point.(ABSTRACT TRUNCATED AT 400 WORDS)