Abstract
Polycyclic aromatic hydrocarbons (PAH), such as benzo(a)pyrene (BP), benz(a)anthracene (BA) and chrysene (C), are widely distributed contaminants in the environment and proven tumorigens in experimental animals. Epidemiological data indicate a role for PAH also in the etiology of certain human tumors1. PAH require metabolic transformation to electrophilic intermediates to exert their toxic effects, most probably through covalent binding of these intermediates to critical targets in DNA. BP is activated through the action of cytochrome P-450-linked monooxygenases and epoxide hydrolase to diastereomeric trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-BP (anti- and syn-BPDE). The (+)-enantiomer of anti-BPDE, with R,S,S,R-absolute configuration, is the most tumorigenic one of the isomers in animals2. Similar results have been obtained with the equivalent diol-epoxides of BA and C3. Furthermore, covalent binding of (+)-anti-BPDE to the exocyclic nitrogen of deoxyguanosine in DNA of target tissues is closely correlated with tumor formation4. Thus, it is likely that enzymatic and non-enzymatic processes that prevent intracellular accumulation of PAH diol-epoxides will counteract DNA-damage and resulting consequences.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
A. Dipple, Polyaromatic hydrocarbon carcinogenesis, in: “Polycyclic Hydrocarbons and Carcinogenesis”, R. G. Harvey, ed., American Chemical Society, Washington, D. C. (1985).
C. S. Cooper, P. L. Grover and P. Sims, The metabolism and activation of benzo(a)pyrene, Prog. Drug Metab. 7:295 (1983).
R. E. Lehr, S. Kumar, W. Levin, A. W. Wood, R. L. Chang, A. H. Conney, H. Yagi, J. M. Sayer and D. M. Jerina, The bay region theory of polycyclic aromatic hydrocarbon carcinogenesis, in: “Polycyclic Hydrocarbons and Carcinogenesis”, R. G. Harvey, ed., American Chemical Society, Washington, D. C. (1985).
J. C. Pelling, T. J. Slaga and J. DiGiovanni, Formation and persistence of DNA, RNA and protein adducts in mouse skin exposed to pure enantiomers of 7ß,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetra-hydrobenzo(a)pyrene in vivo, Cancer Res. 44:1081 (1984).
B. Jernström, J. R. Babson, P. Moldéus, A. Holmgren and D. J. Reed, Glutathione conjugation and DNA-binding of (±)-trans-7,8-di-hydroxy-7,8-dihydrobenzo(a)pyrene and (±)-7ß,8α-dihydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in isolated rat hepatocytes, Carcinogenesis 3:861 (1982).
B. Jernström, M. Martinez, S. Å, and L. Dock, Metabolism of benzo(a)pyrene-7,8-dihydrodiol and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and glutathione conjugates in isolated hepatocytes, Carcinogenesis 5:1079 (1984).
I. G. C. Robertson, H. Jensson, C. Guthenberg, M. K. Tahir, B. Jernström and B. Mannervik, Differences in the occurrence of glutathione transferase isoenzymes in rat lung and liver, Biochem Biophys Res Commun. 127:80 (1985).
M. Warholm, C. Guthenberg, B. Mannervik and C. von Bahr, Purification of a new glutathione S-transferase (transferase μ) from human liver having high activity with benzo(a)pyrene-4,5-oxide, Biochem. Biophys. Res. Commun. 98:512 (1981).
B. Mannervik and C. Guthenberg, Glutathione transferase (human placenta), Methods Enzymol. 77:231 (1981).
W. B. Jakoby, B. Ketterer and B. Mannervik, Glutathione transferases: nomenclature, Biochem. Pharmacol. 33:2539 (1984).
I. G. C. Robertson and B. Jernström, The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo(a)pyrene, benz(a)anthracene, and chrysene, Carcinogenesis 7:1633 (1986).
I. G, C. Robertson, H. Jensson, B. Mannervik and B. Jernström, Glutathione transferases in rat lung: the presence of transferase 7–7, highly efficient in the conjugation of glutathione with the carcinogenic (+)-7ß,-8α-dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydro-benzo(a)pyrene, Carcinogenesis 7:295 (1986).
I. G. C. Robertson, C. Guthenberg, B. Mannervik and B. Jernström, Differences in stereoselectivity and catalytic efficiency of three human glutathione transferases in the conjugation of glutathione with 7ß,8α-dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydrobenzo-(a)pyrene, Cancer Res. 46:2220 (1986).
L. Dock, M. Martinez and B. Jernström, Increased stability of (±)-7ß,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene through interaction with subcellular fraction of rat liver, Chem.-Biol. Interact. 61:31 (1987).
B. Jernström, M. Martinez, D. J. Meyer and B. Ketterer, Glutathione conjugation of the carcinogenic and mutagenic electrophile (±)-7ß,8α-dihydroxy-9α, 10α-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene catalyzed by purified rat liver glutathione transferases, Carcinogenesis 6:85 (1985).
S. K. Yang, D. W. McCourt, P. P. Roeler and H. V. Gelboin, Enzymatic conversion of benzo(a)pyrene leading predominantly to the diolepoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)-pyrene through a single enantiomer of r-7,t-8-dihydroxy-7,8-di-hydrobenzo(a)pyrene, Proc. Natl. Acad. Sci. USA 73:2594 (1976).
B. Mannervik, The isoenzymes of glutathione transferase, Adv Enzymol. 57:357 (1985).
M. Warholm, C. Guthenberg and B. Mannervik, Molecular and catalytic properties of glutathione transferase μ from human liver: an enzyme efficiently conjugating epoxides, Biochemistry 22:3610 (1983).
J.-E. Seidegård, R. W. Pero, D. G. Miller and E. J. Beattie, A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer, Carcinogenesis 7:751 (1986).
T. D. Boyer, D. Zakim and D. A. Vessey, Do soluble glutathione Stransferase have direct access to membrane-bound substrates? Biochem. Pharmacol. 32:29 (1983).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1988 Springer Science+Business Media New York
About this chapter
Cite this chapter
Jernström, B., Robertson, I.G.C., Mannervik, B., Dock, L. (1988). Enzymatic Detoxication of Tumorigenic Bay-Region Diol-Epoxides of Polycyclic Aromatic Hydrocarbons by Conjugation with Glutathione. In: Feo, F., Pani, P., Columbano, A., Garcea, R. (eds) Chemical Carcinogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9640-7_7
Download citation
DOI: https://doi.org/10.1007/978-1-4757-9640-7_7
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-9642-1
Online ISBN: 978-1-4757-9640-7
eBook Packages: Springer Book Archive