ELEVATIONS OF HEPATIC QUINONE REDUCTASE, GLUTATHIONE, AND ALPHA-CLASSAND MU-CLASS GLUTATHIONE-S-TRANSFERASE ISOFORMS IN MICE WITH CHRONIC HEPATITIS - A COMPENSATORY RESPONSE TO INJURY

Hepatic levels of GSH and Phase IT detoxication enzymes were compared to biochemical and histological indices of hepatic damage in 4- to 76- week-old nontransgenic mice and their transgenic littermates that over express the hepatitis B virus large envelope protein. The mice were fe d a low-sucrose AIN-76A diet and libitum. Hepatic-specific activities of quinone reductase (QR) and glutathione S-transferase (GST) were inc reased 2- to 10-fold beginning at 12 weeks of age in transgenic mice a nd correlated with increases in serum alanine aminotransferase (ALT) ( r = 0.84 and 0.59, respectively). Quantitative histological analysis d emonstrated that apoptosis was the predominant feature in 4- to 12-wee k-old transgenic mice, whereas necrosis and inflammation predominated at later time points. Surprisingly, 3-fold elevations in ALT were obse rved beginning at 52 weeks of age in nontransgenic mice, and hepatic-s pecific activities of QR and GST were also modestly increased in elder ly nontransgenic animals. In contrast to transgenic mice, apoptosis wa s not a prominent feature. The strongest histological correlates to AL T in 4- to 76-week-old nontransgenic mice were necrosis and inflammati on (r > 0.96), which in turn may have been evoked by hepatic fat accum ulation. Profiles of specific GST isoforms were quantitated chromatogr aphically and identified by sequencing tryptic digests. The Ya(1) subu nit of alpha-dass GST was markedly increased from undetectable levels in transgenic mice, while more modest increases were observed in nontr ansgenic mice more than 1 year old. Fivefold elevations of the Yb-1 su bunit, a constitutively expressed mu-class GST, were found in transgen ic mice older than 4 weeks of age, while 2-fold increases were observe d in nontransgenic animals that were more than 1 year old. These studi es demonstrate that selected increases in Phase II detoxication enzyme s are a stereotyped response to chronic hepatitis that is strikingly r eminiscent of the treatment of mice with anticarcinogenic enzyme induc ers. (C) 1996 Academic Press, Inc.