A molecular orbital study of the metabolism and carcinogenicity of the phenols of benzo(a)pyrene

Relative tendencies of the twelve isomeric phenol derivatives of benzo(a)pyrene to undergo specific metabolic chemical reactions have been examined using molecular orbital calculations. Considering presumed “activating” reactions alone, the calculations suggest that all the hydroxy derivatives except those substituted on the benzo ring should be capable of forming bay region carbonium ions via epoxide and dihydrodiol intermediates. Oxyradical formation provides a possible competing pathway. The tendency of benzo(a)pyrene phenols to form oxyradicals appears to be strongly influenced by the position of substitution: 6-hydroxybenzo(a)pyrene is calculated to have the highest tendency to undergo this transformation and 2-hydroxybenzo(a)pyrene the lowest tendency. It is suggested that the differing carcinogenic activities of the benzo(a)pyrene phenols may be related to their tendencies to form oxyradicals and that this reaction may provide a deactivating reaction pathway for these compounds.

[1]  G. Cohen,et al.  Metabolism and macromolecular binding of carcinogenic and noncarcinogenic metabolites of benzo(a)pyrene by hamster embryo cells. , 1980, Cancer research.

[2]  P. Seybold,et al.  Substituent effects in chemical carcinogenesis: Methyl derivatives of the benzacridines , 1979 .

[3]  R. Lubet,et al.  The metabolic activation of benzo(a)pyrene and 9‐hydroxybenzo (a) pyrene by liver microsomal fractions , 1979, International journal of cancer.

[4]  A. Gräslund,et al.  Fluorescence study of DNA-complexes formed after metabolic activation of benzo(a)pyrene derivatives. , 1978, Biochemical and biophysical research communications.

[5]  P. Seybold,et al.  Relationships between carcinogenicity and theoretical reactivity indices in polycyclic aromatic hydrocarbons. , 1978, Cancer research.

[6]  S. Orrenius,et al.  Fluorescence study of DNA-binding metabolites of benzo(a)pyrene formed in hepatocytes isolated from 3-methylcholanthrene-treated rats. , 1978, Cancer research.

[7]  E. Miller.  Some current perspectives on chemical carcinogenesis in humans and experimental animals: Presidential Address. , 1978, Cancer research.

[8]  J. Depierre,et al.  The metabolism of polycyclic hydrocarbons and its relationship to cancer. , 1978, Biochimica et biophysica acta.

[9]  Paul G. Seybold,et al.  Correlation of an electronic reactivity index with carcinogenicity in polycyclic aromatic hydrocarbons , 1978 .

[10]  T. Slaga,et al.  Skin tumor-initiating activities of the twelve isomeric phenols of benzo(a)pyrene. , 1978, Cancer research.

[11]  P. Fu,et al.  Molecular orbital theoretical prediction of the isomeric products formed from reactions of arene oxides and related metabolites of polycyclic aromatic hydrocarbons , 1978 .

[12]  D. Jerina,et al.  Nuclear metabolism of benzo(a)pyrene and of (+/-)-trans-7-8-dihydroxy-7-8,-dihydrobenzo(a)pyrene. Comparative chromatographic analysis of alkylated DNA. , 1977, Archives of biochemistry and biophysics.

[13]  D. Jerina,et al.  High carcinogenicity of 2-hydroxybenzo(a)pyrene on mouse skin. , 1977, Cancer research.

[14]  D. Jerina,et al.  THE BAY-REGION THEORY: A QUANTUM MECHANICAL APPROACH TO AROMATIC HYDROCARBON-INDUCED CARCINOGENICITY , 1977 .

[15]  D. Jerina,et al.  Lack of carcinogenicity of 4-, 5-, 6-, 7-, 8-, 9-, and 10-hydroxybenzo(a)pyrene on mouse skin. , 1976, Cancer research.

[16]  M. Thompson,et al.  The role of 9‐hydroxybenzo(a)pyrene in the microsome mediated binding of benzo(a)pyrene to dna , 1976, International journal of cancer.

[17]  A. Y. Lu,et al.  Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes. , 1976, The Journal of biological chemistry.

[18]  P. D. Sullivan,et al.  Free radicals derived from benzo[a]pyrene. , 1976, Biochemical and biophysical research communications.

[19]  J. Selkirk,et al.  Separation of ten benzo(a)pyrene phenols by recycle high pressure liquid chromatography and identification of four phenols as metabolites. , 1976, Biochemical pharmacology.

[20]  J. Selkirk,et al.  Metabolism of benzo(a)pyrene by human epithelial cells in vitro. , 1975, Cancer research.

[21]  W. Caspary,et al.  Autoxidation of 6-hydroxybenzo(a)pyrene and 6-oxobenzo(a)pyrene radical, reactive metabolites of benzo(a)pyrene , 1975 .

[22]  W. Caspary,et al.  Enzymic formation of 6-oxobenzo[a]pyrene radical in rat liver homogenates from carcinogenic benzo[a]pyrene , 1975 .

[23]  D. Jerina,et al.  Mutagenic and cytotoxic activity of benzol[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Selkirk,et al.  High-pressure liquid chromatographic analysis of benzo(alpha)pyrene metabolism and covalent binding and the mechanism of action of 7,8-benzoflavone and 1,2-epoxy-3,3,3-trichloropropane. , 1974, Cancer research.

[25]  A. Y. Lu,et al.  Effects of inducers and epoxide hydrase on the metabolism of benzo(a)pyrene by liver microsomes and a reconstituted system: analysis by high pressure liquid chromatography. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Jerina,et al.  Arene oxides: a new aspect of drug metabolism. , 1974, Science.

[27]  P. Grover,et al.  Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. , 1974, Advances in cancer research.

[28]  H. Gelboin,et al.  K-region and non-K-region metabolism of benzo(a)pyrene by rat liver microsomes. , 1973, Cancer research.

[29]  M. Calvin,et al.  Molecular characteristics of some carcinogenic hydrocarbons. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Adams,et al.  Electrochemical oxidation pathways of benzo [a] pyrene. , 1970, Journal of the American Chemical Society.

[31]  J. D. Memory,et al.  Superdelocalizability indices and the Pullman theory of chemical carcinogenesis , 1967 .

[32]  B. Pullman,et al.  Electronic structure and carcinogenic activity of aromatic molecules; new developments. , 1955, Advances in cancer research.

[33]  L. Fieser,et al.  The Orientation of 3,4-Benzpyrene in Substitution Reactions , 1939 .