Triiodothyronine downregulates the periportal expression of α class glutathione S-transferase in rat liver

Abstract

Most drug-metabolizing phase I and phase II enzymes, including the glutathione S-transferases (GST), exhibit a zonated expression in the liver, with lower expression in the upstream, periportal region. To elucidate the involvement of pituitary-dependent hormones in this zonation, the effect of hypophysectomy and 3,3′,5-triiodo- L-thyronine (T 3) on the distribution of GST was studied in rats. Hypophysectomy increased total GST activity both in the periportal and perivenous liver region. Subsequent T 3 treatment counteracted this effect in the perivenous zone. However, analysis for either μ class M1/M2-specific (1,2-dichloro-4-nitrobenzene) or α class A1/A2-specific (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole) GST activity revealed that T 3 treatment did not significantly affect the perivenous activity of these GST classes. In contrast, T 3 was found to significantly counteract the increase of α class GST activity caused by hypophysectomy in the periportal zone. To establish whether this effect was T 3-specific, hepatocytes were isolated from either the periportal and perivenous zone by digitonin/collagenase perfusion and cultured either as pyruvate-supplemented monolayer or as co-culture with rat liver epithelial cells. Only in the latter it was found that T 3 suppressed the A1/A2-specific GST activity and α class proteins predominantly in periportal cells. The data demonstrate that T 3 is an important factor responsible for the low expression of α GST in the periportal region. T 3 may be involved in the periportal downregulation of other phase I and II enzymes as well.