Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 May;71(5):1130–1140. doi: 10.1172/JCI110863

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

L G Israels, G A Walls, D J Ollmann, E Friesen, E D Israels
PMCID: PMC436974  PMID: 6304144

Abstract

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 K1 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 K1 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 function in the metabolism of benzo(a)pyrene and possibly other compounds metabolized through the mixed function oxidase system.

Full text

PDF
1130

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ASTERIADOU-SAMARTZIS E., LEIKIN S. The relation of vitamin K to hyperbilirubinemia. Pediatrics. 1958 Mar;21(3):397–402. [PubMed] [Google Scholar]
  2. Ames B. N., Mccann J., Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat Res. 1975 Dec;31(6):347–364. doi: 10.1016/0165-1161(75)90046-1. [DOI] [PubMed] [Google Scholar]
  3. Boroujerdi M., Kung H., Wilson A. G., Anderson M. W. Metabolism and DNA binding of benzo(a)pyrene in vivo in the rat. Cancer Res. 1981 Mar;41(3):951–957. [PubMed] [Google Scholar]
  4. CHEN J. M. The cultivation in fluid medium of organised liver, pancreas and other tissues of foetal rats. Exp Cell Res. 1954 Nov;7(2):518–529. doi: 10.1016/s0014-4827(54)80096-6. [DOI] [PubMed] [Google Scholar]
  5. DePierre J. W., Moron M. S., Johannesen K. A., Ernster L. A reliable, sensitive, and convenient radioactive assay for benzpyrene monooxygenase. Anal Biochem. 1975 Feb;63(2):470–484. doi: 10.1016/0003-2697(75)90371-1. [DOI] [PubMed] [Google Scholar]
  6. Duello T. J., Matschiner J. T. Characterization of vitamin K from human liver. J Nutr. 1972 Mar;102(3):331–335. doi: 10.1093/jn/102.3.331. [DOI] [PubMed] [Google Scholar]
  7. ERNSTER L., DANIELSON L., LJUNGGREN M. DT diaphorase. I. Purification from the soluble fraction of rat-liver cytoplasm, and properties. Biochim Biophys Acta. 1962 Apr 9;58:171–188. doi: 10.1016/0006-3002(62)90997-6. [DOI] [PubMed] [Google Scholar]
  8. Esmon C. T., Suttie J. W. Vitamin K-dependent carboxylase. Solubilization and properties. J Biol Chem. 1976 Oct 25;251(20):6238–6243. [PubMed] [Google Scholar]
  9. Feuer G., Kellen J. A., Kovacs K. Suppression of 7,12-dimethylbenz(alpha) anthracene-induced breast carcinoma by coumarin in the rat. Oncology. 1976;33(1):35–39. doi: 10.1159/000225098. [DOI] [PubMed] [Google Scholar]
  10. Gehan E. A. A generalized two-sample Wilcoxon test for doubly censored data. Biometrika. 1965 Dec;52(3):650–653. [PubMed] [Google Scholar]
  11. Gelboin H. V. Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol Rev. 1980 Oct;60(4):1107–1166. doi: 10.1152/physrev.1980.60.4.1107. [DOI] [PubMed] [Google Scholar]
  12. Green A. P., Hooper M., Sweetman A. J. The interaction of 2-phenylisatogen and menadione with rat liver mitochondrial NADH dehydrogenase. Biochem Pharmacol. 1974 May 1;23(11):1569–1576. doi: 10.1016/0006-2952(74)90368-2. [DOI] [PubMed] [Google Scholar]
  13. Hlavica P., Kehl M. Studies on the mechanism of hepatic microsomal N-oxide formation. The role of cytochrome P-450 and mixed-function amine oxidase in the N-oxidation of NN-dimethylaniline. Biochem J. 1977 Jun 15;164(3):487–496. doi: 10.1042/bj1640487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holder G. M., Yagi H., Jerina D. M., Levin W., Lu A. Y., Conney A. H. Metabolism of benzo[a]pyrene. Effect of substrate concentration and 3-methylcholanthrene pretreatment on hepatic metabolism by microsomes from rats and mice. Arch Biochem Biophys. 1975 Oct;170(2):557–566. doi: 10.1016/0003-9861(75)90151-4. [DOI] [PubMed] [Google Scholar]
  15. Israels E. D., Papas A., Campbell L. D., Israels L. G. Prevention by menadione of the hepatotoxic effects in chickens fed rapeseed meal. Observations on coagulation factors and cytochrome P-450. Gastroenterology. 1979 Mar;76(3):584–589. [PubMed] [Google Scholar]
  16. Kupfer D., Peets L. Inhibition of cortisol metabolism in vitro by 2-methylnaphthoquinone (menadione): a possible interpretation of the potentiation of cortisol activity in vivo. Experientia. 1968 Sep 15;24(9):893–894. doi: 10.1007/BF02138634. [DOI] [PubMed] [Google Scholar]
  17. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  18. Lin J. K., Kennan K. A., Miller E. C., Miller J. A. Reduced nicotinamide adenine dinucleotide phosphate-dependent formation of 2,3-dihydro-2,3-dihydroxyaflatoxin B1 from aflatoxin B1 by hepatic microsomes. Cancer Res. 1978 Aug;38(8):2424–2428. [PubMed] [Google Scholar]
  19. Lind C., Vadi H., Ernster L. Metabolism of benzo(a)pyrene-3,6-quinone and 3-hydroxybenzo(a)pyrene in liver microsomes from 3-methylcholanthrene-treated rats. A possible role of DT-diaphorase in the formation of glucuronyl conjugates. Arch Biochem Biophys. 1978 Sep;190(1):97–108. doi: 10.1016/0003-9861(78)90256-4. [DOI] [PubMed] [Google Scholar]
  20. MAMEESH M. S., JOHNSON B. C. Production of dietary vit. K deficiency in the rat. Proc Soc Exp Biol Med. 1959 Jul;101(3):467–468. doi: 10.3181/00379727-101-24982. [DOI] [PubMed] [Google Scholar]
  21. Nebert D. W., Gelboin H. V. The in vivo and in vitro induction of aryl hydrocarbon hydroxylase in mammalian cells of different species, tissues, strains, and developmental and hormonal states. Arch Biochem Biophys. 1969 Oct;134(1):76–89. doi: 10.1016/0003-9861(69)90253-7. [DOI] [PubMed] [Google Scholar]
  22. Sadowski J. A., Esmon C. T., Suttie J. W. Vitamin K-dependent carboxylase. Requirements of the rat liver microsomal enzyme system. J Biol Chem. 1976 May 10;251(9):2770–2776. [PubMed] [Google Scholar]
  23. Selkirk J. K., Croy R. G., Gelboin H. V. Benzo(a)pyrene metabolites: efficient and rapid separation by high-pressure liquid chromatography. Science. 1974 Apr 12;184(4133):169–171. doi: 10.1126/science.184.4133.169. [DOI] [PubMed] [Google Scholar]
  24. TAYLOR J. D., MILLAR G. J., WOOD R. J. A comparison of the concentration of C14 in the tissues of pregnant and nonpregnant female rats following the intravenous administration of vitamin K1-C14 and vitamin K3-C14. Can J Biochem Physiol. 1957 Sep;35(9):691–697. [PubMed] [Google Scholar]
  25. Wallin R., Suttie J. W. Vitamin K-dependent carboxylation and vitamin K epoxidation. Evidence that the warfarin-sensitive microsomal NAD(P)H dehydrogenase reduces vitamin K1 in these reactions. Biochem J. 1981 Mar 15;194(3):983–988. doi: 10.1042/bj1940983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wills E. D. Effects of vitamin K and naphthoquinones on lipid peroxide formation and oxidative demethylation by liver microsomes. Biochem Pharmacol. 1972 Jul 1;21(13):1879–1883. doi: 10.1016/0006-2952(72)90184-0. [DOI] [PubMed] [Google Scholar]
  27. Wills E. D. Lipid peroxide formation in microsomes. General considerations. Biochem J. 1969 Jun;113(2):315–324. doi: 10.1042/bj1130315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yang S. K., Gelboin H. V. Nonenzymatic reduction of benzo(a)pyrene diol-epoxides to trihydroxypentahydrobenzo(a)pyrenes by reduced nicotinamide adenine dinucleotide phosphate. Cancer Res. 1976 Nov;36(11 Pt 1):4185–4189. [PubMed] [Google Scholar]
  29. Yen C. S., Mack D. O. Solubilized rat liver vitamin K carboxylase demonstrates little selectivity between vitamin K1 and the menaquinones. Proc Soc Exp Biol Med. 1980 Nov;165(2):306–308. doi: 10.3181/00379727-165-40975. [DOI] [PubMed] [Google Scholar]
  30. Young J. M. Comparison of the effects of menadione and 2,3-dimethylnaphthoquinone on the energy-coupling reactions of beef-heart mitochondria. Evidence for the involvement of a thiol group in the reactions of oxidative phosphorylation. Biochem Pharmacol. 1971 Jan;20(1):163–171. doi: 10.1016/0006-2952(71)90482-5. [DOI] [PubMed] [Google Scholar]
  31. ZINKHAM W. H. An in-vitro abnormality of glutathione metabolism in erythrocytes from normal newborns: mechanism and clinical significance. Pediatrics. 1959 Jan;23(1 Pt 1):18–32. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES