Metabolic Activation Of Polycyclic Hydrocarbons Research Articles

Chemical rearrangement of phenol-epoxide metabolites of polycyclic aromatic hydrocarbons to quinone-methides

Evidence for the involvement of triol-epoxide and phenol-epoxide metabolites in the metabolic activation of polycyclic hydrocarbons is accumulating. It is proposed that the phenolic OH-groups present in such epoxides will activate the epoxide moieties and permit their rearrangement to quinone-methides. These quinone-methides are highly reactive, potentially-isolable chemical entities with strong alkylating activity. In one resonance form they are resonance-stabilized carbonium ions. Only epoxides that also possess phenolic OH-groups in certain positions will form quinone-methides: these appear to include 9-hydroxybenzo[a] pyrene 4,5-oxide and the triol-epoxides 9-hydroxy- trans -1,2-dihydro-1,2-dihydroxychrysene 3,4-oxide and 2-hydroxy- trans -9,10-dihydro-9,10-dihydroxybenzo[a]pyrene 7,8-oxide.

The biochemical and genetic characteristics of murine ovarian aryl hydrocarbon (Benzo[ a]pyrene) hydroxylase activity and its relationship to primordial oocyte destruction by polycyclic aromatic hydrocarbons

Primordial oocyte destruction by polycyclic aromatic hydrocarbons requires metabolic activation of the polycyclic hydrocarbon to an ovotoxic metabolite. The first and perhaps subsequent step(s) in the metabolism of polycyclic aromatic hydrocarbons to the proximate ovotoxin occurs via a microsomal cytochrome P-450-dependent monooxygenase. The role of aryl hydrocarbon (benzo[ a]pyrene) hydroxylase (AHH, EC 1.14.14.2) in activation of polycyclic hydrocarbons to ovotoxic products was studied in 11 inbred and two F 1 heterozygote murine strains. The polycyclic aromatic hydrocarbon responsive C57BL/6N and C57BL/6J mice had two- to threefold increases in ovarian AHH activity after polycyclic hydrocarbon treatment. The polycyclic aromatic hydrocarbon nonresponsive DBA/2N and DBA/2J mice had no change in ovarian AHH activity after similar polycyclic hydrocarbon treatment. The polycyclic aromatic hydrocarbon responsive C57BL/6N and C57BL/6J mice had more rapid primordial oocyte destruction after polycyclic hydrocarbon treatment than the nonresponsive DBA/2N and DBA/2J mice. The (DBA/2N)(C57BL/6N)F 1 and (DBA/2J)(C57BL/6J)F 1 mice were responsive to polycyclic hydrocarbons with two- to threefold increases in ovarian AHH activity after treatment, however, the rate of oocyte destruction was similar to that observed in the nonresponsive DBA/2N and DBA/2J mice. Survey of seven additional inbred strains of mice failed to demonstrate a strong correlation between either absolute ovarian AHH activity or fold induction of ovarian AHH activity and oocyte destruction. Similarly, treatment with 2,3,7,8-tetrachlorodibenzo- p-dioxin, a potent inducer of ovarian AHH activity in both polycyclic hydrocarbon responsive and nonresponsive strains, did not alter the rate of oocyte destruction after treatment with benzo[ a]pyrene or 3-methylcholanthrene. Although metabolic activation of polycyclic aromatic hydrocarbons to an ovotoxin is necessary for primordial oocyte destruction, strain differences in sensitivity to oocyte destruction reflect the biological sum of activation, detoxification, and repair. Therefore, differences in ovarian AHH activity or inducibility may not reflect differences in oocyte destruction after polycyclic hydrocarbon treatment.

Microsomal and nuclear metabolism of 3-methylcholanthrene

Hepatic nuclei and microsomes prepared from rats pretreated with 3-methyleholanthrene, or hepatic nuclei prepared from untreated rats, were incubated with generally 3H-labeled 3-methylcholanthrene in the presence of an NADPH-generating system. The metabolic products formed by these three systems were analyzed by high pressure liquid Chromatographie techniques and the products were comparable, both qualitatively and quantitatively. The metabolic formation, from both nuclei and microsomes, of radioactive products corresponding to the cis-1,2- and 11,12-diol,the trans-4,5-,9,10-and 11,12-dihydrodiol,and the 1-and 2-hydroxy and 1- and 2-ketone derivatives of 3-methyleholanthrene was observed when these metabolites were compared, on high pressure liquid chromatographs, with authentic compounds. Pretreatment of the rats with 3-methyleholanthrene resulted in a marked increase in nuclear metabolism, particularly in the formation of 2-hydroxy-3-methylcholanthrene. These studies further reinforce the importance of the nucleus in the metabolic activation of polycyclic hydrocarbons.

Metabolic activation of polycyclic hydrocarbons. Fluorescence spectral evidence is consistent with metabolism at the 1,2- and 3,4-double bonds of 7-methylbenz[a]anthracene.

FEBS LettersVolume 75, Issue 1-2 p. 9-12 Full-length articleFree Access Metabolic activation of polycyclic hydrocarbons Fluorescence spectral evidence is consistent with metabolism at the 1,2- and 3,4-double bonds of 7-methylbenz[a]anthracene1 P. Vigny, P. Vigny Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorM. Duquesne, M. Duquesne Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorH. Coulomb, H. Coulomb Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorC. Lacombe, C. Lacombe Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorB. Tierney, B. Tierney Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, EnglandSearch for more papers by this authorP.L. Grover, P.L. Grover Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, England To whom correspondence should be addressed Search for more papers by this authorP. Sims, P. Sims Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, EnglandSearch for more papers by this author P. Vigny, P. Vigny Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorM. Duquesne, M. Duquesne Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorH. Coulomb, H. Coulomb Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorC. Lacombe, C. Lacombe Fondation Curie-Institut du Radium, Laboratoire Curie, 11, Rue Pierre et Marie Curie, 75231, Paris, Cedex 05, FranceSearch for more papers by this authorB. Tierney, B. Tierney Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, EnglandSearch for more papers by this authorP.L. Grover, P.L. Grover Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, England To whom correspondence should be addressed Search for more papers by this authorP. Sims, P. Sims Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London SW3 6JB, EnglandSearch for more papers by this author First published: March 15, 1977 https://doi.org/10.1016/0014-5793(77)80041-0Citations: 35 To whom correspondence should be addressed 1 The authors would like to dedicate this paper to the memory of Mme Pascaline Daudel who died in Paris on May 12th 1976 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat References 1 P. Daudel, M. Croisy-Delcey, C. Alonso-Verduras, M. Duquesne, P. Jacquignon, P. Markovits, P. Vigny, C. R. Acad. Sci., 278, (1974), 2249– 2252. 2 P. Daudel, H. Kawamura, M. Croisy-Delcey, M. Duquesne, P. Jacquignon, C. R. Acad. Sci., 280, (1975), 521– 524. 3 P. Daudel, M. Duqesne, P. Vigny, P.L. Grover, P. Sims, FEBS Lett., 57, (1975), 250– 253. 4 J. Booth, P. Sims, FEBS Lett., 47, (1974), 30– 33. 5 P. Sims, P.L. Grover, A. Swaisland, K. Pal, A. Hewer, Nature, 252, (1974), 326– 328. 6 P.L. Grover, K. Pal, A. Hewer, P. Sims, Int. J. Cancer, 18, (1976), 1– 6. 7 P. Sims, Biochem. J., 105, (1967), 591– 598. 8 Tierney, B. and Sims, P. manuscript in preparation. 9 P. Sims, Biochem. Pharmacol., 19, (1970), 795– 818. 10 E.R.M. Kay, N.S. Simmons, A.L. Dounce, J. Am. Chem. Soc., 74, (1952), 1724– 1726. 11 P. Vigny, M. Duquesne, Photochem. Photobiol., 20, (1974), 15– 25. 12 W.M. Baird, A. Dipple, P.L. Grover, P. Sims, P. Brookes, Cancer Res., 33, (1973), 2386– 2392. 13 P.L. Grover, A. Hewer, P. Sims, Biochem. Pharmacol., 23, (1973), 323– 332. 14 Marquardt, H., Baker, S., Tierney, B., Grover, P. L. and Sims, P. (1977) submitted for publication. 15 Malaveille, C., Tierney, B., Grover, P. L., Sims, P. and Bartsch, H. (1977) submitted for publication. 16 Chouroulinkov, I. and Gentil, A. personal communication. Citing Literature Volume75, Issue1-2March 15, 1977Pages 9-12 ReferencesRelatedInformation

Malignant transformation in vitro of mouse fibroblasts by 7, 12‐dimethylbenz(A)anthracene and 7‐hydroxymethylbenz(A)anthracene and by their K‐region derivatives

AbstractK‐region epoxides derived from 7, 12‐dimethylbenz(a)anthracene and from 7‐hydroxymethlybenz(a)anthracene were tested for their ability to induce malignant transformation of the M2 clone of fibroblasts derived from C3H mouse prostate. The parent hydrocarbons, the corresponding K‐region dihydrodiols and a phenol were also tested with these cells. The K‐region epoxides induced transformation but were somewhat less active than the hydrocarbons; the ring‐hydroxylated derivatives were inactive. In other experiments, the addition of α‐naphthoflavone was found to inhibit the formation of water‐soluble metabolites from and the toxicity of 7, 12‐dimethylbenz(a)anthracene without affecting malignant transformation. The results are discussed in relation to current theories regarding the metabolic activation of polycyclic hydrocarbons.

K-region epoxides of polycyclic hydrocarbons: Formation and further metabolism by rat-lung preparations

Epoxides of 7-methylbenz[a]anthracene and of benzo[a]pyrene that have been identified as the K-region epoxides, 7-methylbenz[a]anthracene 5,6-oxide and benzo[a]pyrene 4,5-oxide, have been detected as microsomal metabolites using preparations from the lungs of rats that had been pretreated with the microsomal mixed function oxidase inducer, 3-methylcholanthrene. It was also possible, using lung microsomal preparations from uninduced animals, to demonstrate the formation of an epoxide identified as the K-region derivative, benz[a]anthracene 5,6-oxide, as a microsomal metabolite of benz[a]anthracene. The K-region epoxides of 7-methylbenz[a]anthracene and of benzo[a]pyrene could not always be detected as metabolites when lung microsomal preparations from uninduced rats were used. The activities of two other enzymes present in pulmonary tissue fractions that are involved in the further metabolism of polycyclic hydrocarbon epoxides have also been measured and the values compared with those obtained with rat-liver. When benz[a]anthracene 5,6-oxide was used as substrate, much lower levels of microsomal epoxide hydrase activity were found in lung than in liver, but soluble-supernatant fractions of rat-lung appeared to possess higher levels of glutathione S-epoxide transferase activity than were present in rat-liver. The significance of these results in relation to the metabolic activation of polycyclic hydrocarbons by epoxide formation and to the induction of tumours of the respiratory tract by members of this class of chemical carcinogens is discussed.