Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Abstract

A B S T R A C T Vitamin K3 inhibits the conversion of benzo(a)pyrene to its more polar metabolites in an in vitro rat liver microsomal system. Vitamin K3 also inhibits benzo(a)pyrene metabolism in rat liver fragments and reduces its mutagenicity in the Ames test. Higher concentrations of vitamin K3 are required to comparably reduce benzo(a)pyrene metabolism when the microsomal system has been induced with 3-methylcholanthrene. High pressure liquid chromatography analysis of the products of benzo(a)pyrene metabolism shows a uniform reduction of all the metabolic products. When tumors were induced in ICR/Ha female mice by the intraperitoneal injection of benzo(a)pyrene, those mice given vitamin K3 before or both before and after benzo(a)pyrene had a slower rate of tumor appearance and tumor death rate as compared with those receiving benzo(a)pyrene alone. However, vitamin K, increased the rate of tumor death while vitamin K deprivation and warfarin decreased the rate of tumor appearance and death in benzo(a)pyrene-injected mice.These studies indicate that vitamin K3 is an inhibitor of aryl hydrocarbon hydroxylase and reduces the carcinogenic and mutagenic metabolites in vitro, and inhibits benzo(a)pyrene tumorigenesis in vivo. That vitamin K, enhances the benzo(a)pyrene effect while warfarin and vitamin K deficiency inhibit benzo(a)pyrene tumorigenesis indicates that vitamin K1, vitamin K deprivation, or possibly blockade of its metabolic cycle also modulates benzo(a)pyrene metabolism in vivo but by a mechanism or at a site different from the vitamin K3 effect. The vitamin K series should be considered as capable of serving a regulatory func-

Antenatal Drugs Affecting Vitamin K Status of the Fetus and the Newborn

“…In an experimental model, vitamin K 1 was shown by Israels and coworkers to accelerate carcinogen-induced tumourigenesis in mice. 75 The same group showed vitamin K 1 to increase sister chromatid exchange in leukocytes from human adult and cord blood in vitro, and in fetal sheep leukocytes in vivo. 76 Sister chromatid exchange represents the interchange of DNA at homologous chromosomal loci and is dependent both on chromosomal breakage and repair.…”

Vitamin K-Dependent Processes in Tumor Cells

“…Further insight into the warfarin effect was gained through the demonstration that dietary vitamin K deficiency alone inhibited pulmonary métastases of Lewis lung carci noma in the mouse [39,41], Vitamin K] was also shown to reverse the warfarin antimetastatic effect in the KHT sarcoma model sys tem [5]. In the rat, benzo(a)pyrene-induced tumorigenesis and death was reduced by war farin or vitamin K depletion and accelerated by vitamin K.| [98], Direct effects of anticoagulants on tumor cells have been reported from in vitro stud ies. Cultured human malignant glial cells were effectively inhibited by 10~10 M warfa rin [47], At higher concentrations warfarin is cytocidal to mouse tumor cells [5].…”

Electrochemical Studies of Vitamin K3 Interacting with Hemoglobin and Determination of Hemoglobin

“…Much interest has been generated in its potential as a clinically useful antitumor agent. In vitro and in vivo anima data suggest that vitamin K 3 prevents activation of certain carcinogens, such as benzo(a)pyrene and quinazoline, by rat liver [7,8], and reduces the number of benzo(a)pyreneinduced tumors in rats [7]. Vitamin K 3 is a naphthoquinone derivative that is an active electron acceptor in biological and chemical electron-transfer reactions.…”