Manipulation of mouse organ glutathione contents. II: Time and dose-dependent induction of the glutathione conjugation system by phenolic antioxidants.

After 14 days of oral butylated hydroxyanisole (BHA) administration (1000 mg/kg/day) the tissue glutathione levels of male NMRI mice were increased by 74-141% in liver, lung, duodenum and intestine and after similar butylated hydroxytoluene (BHT) treatment by 18-85% in the liver, lung, spleen and the gastrointestinal tract. Doses of 100 mg/kg/day significantly elevated the glutathione content in the lung (BHA, BHT), duodenum (BHA) and intestine (BHA), while 10 mg/kg/day affected only lung glutathione content (BHA). BHA treatment (1000 mg/kg/day) induced GST activities significantly (138-1335%) in all organs investigated except the spleen, i.e. liver, lung, kidney and the entire gastrointestinal tract, while a similar dose of BHT increased GST activities in the liver, duodenum, intestine and colon by 26-339%. Daily doses of 100 mg/kg/day significantly induced GST activities only in the liver (BHA, BHT), lung (BHA) and kidney (BHA). Lower doses of BHA or BHT did not significantly affect GST activities in the organs investigated (except 10 mg BHA/kg/day in the lung). Comparison of the time course of induction of the glutathione conjugation system in various organs after different doses of antioxidants indicated no change between 5 and 14 days of treatment with all doses used (1-1000 mg/kg). Only the lung glutathione level showed a tendency to increase with low dose BHA by extending the time of treatment. The time course of the liver glutathione content between single doses of 100 mg/kg BHA or BHT revealed an initial decline followed by an increase above control values 2 days (BHA) or 5 days (BHT) after the first application. The glutathione levels of the lung and the duodenum increased without a preceding decline. Only the second dose of BHT caused a temporary decrease to control values of the elevated glutathione level in the duodenum. All animals (at any dose of BHA or BHT) showed control values of serum transaminase activities. These results suggest: The induction threshold of the glutathione conjugation system in various mouse organs is greater than or equal to 100 mg/kg for BHA and BHT. Chronic administration of these compounds did not change these results (except the lung glutathione level after low dose BHA). Elevated hepatic glutathione levels might be the result of an activated synthesis caused by a preceding loss of glutathione. Chronic BHA or BHT treatment did not cause hepatotoxic effects, as evaluated by serum transaminases, in male mice.