The Deletion of Kynurenine Hydroxylase Activity During Hepatocarcinogenesis2

Abstract

To determine whether hepatomas retained the enzymatic capability to convert kynurenine to 3-hydroxykynurenine, kynurenine hydroxylase activity was measured in a spectrum of transplanted tumors carried in both rats and mice; in primary hepatomas induced with 4-dimethylaminoazobenzene (DAB), 3′methyl-DAB (3′Me-DAB), and 4′fluoro-DAB (4′F-DAB); and in the livers of animals fed diets containing 3′Me-DAB or the relatively weak carcinogen 4′methyl-DAB (4′Me-DAB). The enzyme activities of both normal and malignant tissues were assayed in mitochondria isolated by differential centrifugation and disrupted by treatment with digitonin. No kynurenine hydroxylase activity was detected in 4 transplanted rat hepatomas, in 2 transplanted mouse hepatomas, or in primary hepatomas induced in rat liver. The absence of activity in hepatomas was not associated with endogenous inhibitors or with the absence of essential activators in whole or soluble fraction mitochondria isolated from normal liver. Also ineffective were several compounds which were possible activators or co-factors for kynurenine hydroxylase. The kynurenine hydroxylase activity of animals maintained on a basal riboflavine-deficient diet, or this diet plus 0.06 percent 3′Me-DAB, or basal diet with 0.06 percent 4′Me-DAB, was determined at 4-week intervals throughout 12 weeks. All 3 groups sustained losses, which were heaviest in the group fed 3′Me-DAB and less severe in the group fed 4′Me-DAB. Hydroxylase activity changed least in the group maintained on the riboflavine-deficient basal diet. We concluded that factors in addition to those associated with malignant transformation altered the kynurenine hydroxylase activity of precancerous liver.—J Nat Cancer Inst 30: 675–686, 1963.