Placental Glutathione S-Transferase (GST-P) as a New Marker for Hepatocarcinogenesis: In Vivo Short-Term Screening for Hepatocarcinogens

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Abstract
Our laboratory has developed an in vivo short-term screening test for hepatocarcinogens based on quantitation of γ-glutamyl transpeptidase (γ-GT) positive foci. However, γ-GT positive hepatocytes appear in periportal areas under a variety of circumstances apparently unrelated to hepatocarcinogenesis. Glutathione S-transferase placental type (GST-P), which is hardly detectable in normal rat liver, was recently demonstrated as a new marker protein for preneoplastic liver foci. In experiment I, rats were initially given a single dose (200 mg/kg) of diethylnitrosamine intraperitoneally and 2 weeks later were treated with test compounds for 6 weeks. All rats were subjected to partial hepatectomy at week 3. The long-term development of preneoplastic lesions was followed in rats for 50 weeks. The immunohistochemical investigation of GST-P binding and the histochemical demonstration of γ-GT in serial sections revealed that almost all γ-GT foci were GST-P positive, but 5–10% of GST-P foci could not be detected by γ-GT staining. From week 8, many γ-GT foci partially lost γ-GT activity. However, no comparable disappearance of GST-P was evident in the lesions. All hepatocellular carcinomas (HC) found at week 50 consisted of GST-P positive HC cells. In contrast, 37.9% (11/29) of HC were negative for γ-GT. In experiment II (in vivo short-term screening test for hepatocarcinogens), rats were treated in the same manner as for experiment I and killed at week 8. Fifty-eight chemicals were investigated for their potential to modify GST-P positive foci development. All hepatocarcinogens and hepatopromoters clearly enhanced the induction of GST-P foci, whereas non-hepatocarcinogens and non-hepatopromoters did not. BHA and acetaminophen inhibited the development of foci. These results suggest the adoption of GST-P as a new and more accurate marker enzyme for rat liver carcinogenesis.

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