Chemically induced rat liver nodules and
cancers characteristically demonstrate a limited capacity to activate
xenobiotics to reactive species mainly because of decreased amounts of
cytochrome P-450. These lesions also show enhancement of
xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver
tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for
carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and
diethylnitrosamine-induced mouse liver
tumors for nine
enzyme activities commonly reported to be altered in chemically induced rat liver nodules and
cancers. The activities of
benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase,
cytochrome P-450 reductase,
epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl
transferase (EC 2.4.1.17) in microsomes from spontaneous
tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced
tumors. The activities of
DT-diaphorase (EC 1.6.99.2),
glutathione reductase (EC 1.6.4.2),
glutathione S-transferase (EC 2.5.1.18), and
glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous
tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced
tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and
cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver
tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.