Biochemical features of spontaneous hepatic tumors in C3H mice were studied histochemically in comparison with those of neoplastic lesions developed in animals fed dietary phenobarbital (PB) continuously or treated with diethylnitrosamine (DEN) during 11-14 weeks of age. All 42 spontaneous hepatic tumors that developed in control mice by 74 weeks of age were completely negative for γ-glutamyl transpeptidase (γ-GTPase) activity. Dietary phenobarbital enhanced hepatic tumorigenesis remarkably,

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... 32 out of 43 tumors found at 70 weeks showed multifocal γ-GTPase activity. DEN induced γ-GTPase-positive islands of hepatocytes, but 12 out of 13 tumors larger than 5mm in diameter that developed by 60 weeks were γ-GTPasenegative. The phenomenon of induction of γ-GTPase activity by PB in "spontaneous" hepatic tumors appears to be important both for elucidating the mechanism of promotion by PB and also for analyzing multisteps of carcinogenesis.