Heme Enzyme Patterns in Rat Liver Nodules and Tumors1

Chemically induced rat bepatocyte nodules and carcinomas have a reduced capacity to oxidize drugs. The reduction in monooxygenase activity results largely from the partial loss of cytochrome P-450, a hemecontaining terminal electron acceptor. To determine whether the cyto chrome P-450 deficit was indicative of an altered heme metabolism, we quantitated four heme-containing proteins in normal rat liver and in rat liver nodules and cancers induced by 2-acetylaminofluorene or dicthylnitrosamine: cytochrome P-450; cytochrome b¿catalase (EC 1.11.1.6); and tryptophan 2,3-dioxygenase (EC 1.13.11.11). The amounts of these components in nodules were 45%, 88%, 50%, and 59% of normal liver, respectively, in 2-acetylaminofluorene-inducedcancers, 65%, 74%, 64%, and 65%, respectively, and in diethylnitrosamine-inducedcancers, 40%, 69%, 56%, and 52%. 5-Aminolevulinic acid synthase (EC 23.1 J7), the rate-limiting enzyme in the heme synthetic pathway,and heme oxygenase (EC 1.14.99.3), a degradativi? enzyme, were also quantitated. The amounts of these enzymes in nodules were 95% and 138% of normal liver, respectively, whereas in 2-acetylaminofluorene-induced cancers, they were 47% and 233%, and in diethylnitrosamine-induced cancers, they were 50% and 175%. These data indicate that four nonmitochondrial liver hemoproteins were diminished to about the same extent in hepatic nodules and cancers. Nodules and cancers also demonstratedan increased capacity for heme degradation, while cancers also demonstrated a de creased capacity for heme synthesis. Thus, the resistance of nodules and tumors to P-450-activated cytotoxic agents may ultimately result from a disturbance in heme metabolism.