Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Sep;76(9):4280–4284. doi: 10.1073/pnas.76.9.4280

Differences in mutagenicity and cytotoxicity of (+)- and (-)-benzo[a]pyrene 4,5-oxide: a synergistic interaction of enantiomers.

R L Chang, A W Wood, W Levin, H D Mah, D R Thakker, D M Jerina, A H Conney
PMCID: PMC411557  PMID: 388437

Abstract

In order to study the biological effects of (+)- and (-)-benzo[a]pyrene 4,5-oxide, a synthesis of these molecules has been developed based on the resolution of (+/-)-cis-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene. The (-) enantiomer of benzo[a]pyrene 4,5-oxide was 1.5- to 5.5-fold more mutagenic than the (+) enantiomer in strains TA 98, TA 100, TA 1537, and TA 1538 of Salmonella typhimurium and in Chinese hamster V79 cells. In studies with V79 Cells, the (-) enantiomer of benzo[a]pyrene 4,5-oxide was also more cytotoxic than the (+) enantiomer. When mixtures of the enantiomers were studied in V79 cells, synergistic cytotoxic and mutagenic responses were observed. The greatest cytotoxic and mutagenic effects occurred with a 3:1 mixture of the (-) and (+) enantiomers of benzo[a]pyrene 4,5-oxide, respectively.

Full text

PDF
4280

Selected References

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

  1. Ames B. N., Durston W. E., Yamasaki E., Lee F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2281–2285. doi: 10.1073/pnas.70.8.2281. [DOI] [PMC free article] [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. Buening M. K., Wislocki P. G., Levin W., Yagi H., Thakker D. R., Akagi H., Koreeda M., Jerina D. M., Conney A. H. Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5358–5361. doi: 10.1073/pnas.75.11.5358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chu E. H., Malling H. V. Mammalian cell genetics. II. Chemical induction of specific locus mutations in Chinese hamster cells in vitro. Proc Natl Acad Sci U S A. 1968 Dec;61(4):1306–1312. doi: 10.1073/pnas.61.4.1306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dansette P., Jerina D. M. A facile synthesis of arene oxides at the K regions of polycylic hydrocarbons. J Am Chem Soc. 1974 Feb 20;96(4):1224–1225. doi: 10.1021/ja00811a046. [DOI] [PubMed] [Google Scholar]
  6. Grover P. L., Hewer A., Sims P. Formation of K-region epoxides as microsomal metabolites of pyrene and benzo(a)pyrene. Biochem Pharmacol. 1972 Oct 15;21(20):2713–2726. doi: 10.1016/0006-2952(72)90020-2. [DOI] [PubMed] [Google Scholar]
  7. Holder G., Yagi H., Dansette P., Jerina D. M., Levin W., Lu A. Y., Conney A. H. 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. Proc Natl Acad Sci U S A. 1974 Nov;71(11):4356–4360. doi: 10.1073/pnas.71.11.4356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Huberman E., Sachs L. Cell-mediated mutagenesis of mammalian cells with chemical carcinogens. Int J Cancer. 1974 Mar 15;13(3):326–333. doi: 10.1002/ijc.2910130308. [DOI] [PubMed] [Google Scholar]
  9. Huberman E., Sachs L., Yang S. K., Gelboin V. Identification of mutagenic metabolites of benzo(a)pyrene in mammalian cells. Proc Natl Acad Sci U S A. 1976 Feb;73(2):607–611. doi: 10.1073/pnas.73.2.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Levin W., Wood A. W., Yagi H., Dansette P. M., Jerina D. M., Conney A. H. Carcinogenicity of benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides on mouse skin. Proc Natl Acad Sci U S A. 1976 Jan;73(1):243–247. doi: 10.1073/pnas.73.1.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Malaveille C., Kuroki T., Sims P., Grover P. L., Bartsch H. Mutagenicity of isomeric diol-epoxides of benzo[a]pyrene and benz[a]anthracene in S. typhimurium TA98 and TA100 and in V79 Chinese hamster cells. Mutat Res. 1977 Sep;44(3):313–326. doi: 10.1016/0027-5107(77)90091-4. [DOI] [PubMed] [Google Scholar]
  12. McCann J., Spingarn N. E., Kobori J., Ames B. N. Detection of carcinogens as mutagens: bacterial tester strains with R factor plasmids. Proc Natl Acad Sci U S A. 1975 Mar;72(3):979–983. doi: 10.1073/pnas.72.3.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Newbold R. F., Brookes P. Exceptional mutagenicity of a benzo(a)pyrene diol epoxide in cultured mammalian cells. Nature. 1976 May 6;261(5555):52–54. doi: 10.1038/261052a0. [DOI] [PubMed] [Google Scholar]
  14. Selkirk J. K., Croy R. G., Gelboin H. V. Isolation by high pressure liquid chromatography and characterization of benzo(a)pyrene-4'5-epoxide as a metobolite of benzoapyrene. Arch Biochem Biophys. 1975 May;168(1):322–326. doi: 10.1016/0003-9861(75)90256-8. [DOI] [PubMed] [Google Scholar]
  15. Slaga T. J., Bracken W. J., Gleason G., Levin W., Yagi H., Jerina D. M., Conney A. H. Marked differences in the skin tumor-initiating activities of the optical enantiomers of the diastereomeric benzo(a)pyrene 7,8-diol-9,10-epoxides. Cancer Res. 1979 Jan;39(1):67–71. [PubMed] [Google Scholar]
  16. Wislocki P. G., Wood A. W., Chang R. L., Levin W., Yagi H., Hernandez O., Dansette P. M., Herina D. M., Conney A. H. Mutagenicity and cytotoxicity of benzo(a)pyrene arene oxides, phenols, quinones, and dihydrodiols in bacterial and mammalian cells. Cancer Res. 1976 Sep;36(9 PT1):3350–3357. [PubMed] [Google Scholar]
  17. Wood A. W., Chang R. L., Levin W., Lehr R. E., Schaefer-Ridder M., Karle J. M., Jerina D. M., Conney A. H. Mutagenicity and cytotoxicity of benz[alpha]anthracene diol epoxides and tetrahydro-epoxides: exceptional activity of the bay region 1,2-epoxides. Proc Natl Acad Sci U S A. 1977 Jul;74(7):2746–2750. doi: 10.1073/pnas.74.7.2746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wood A. W., Chang R. L., Levin W., Yagi H., Thakker D. R., Jerina D. M., Conney A. H. Differences in mutagenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides. Biochem Biophys Res Commun. 1977 Aug 22;77(4):1389–1396. doi: 10.1016/s0006-291x(77)80133-2. [DOI] [PubMed] [Google Scholar]
  19. Wood A. W., Goode R. L., Chang R. L., Levin W., Conney A. H., Yagi H., Dansette P. M., Jerina D. M. Mutagenic and cytotoxic activity of benzol[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3176–3180. doi: 10.1073/pnas.72.8.3176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Wood A. W., Wislocki P. G., Chang R. L., Levin W., Lu A. Y., Yagi J., Hernandez O., Herina D. M., Conney A. H. Mutagenicity and cytotoxicity of benzo(a)pyrene benzo-ring epoxides. Cancer Res. 1976 Sep;36(9 PT1):3358–3366. [PubMed] [Google Scholar]
  21. Yagi H., Akagi H., Thakker D. R., Mah H. D., Koreeda M., Jerina D. M. Absolute sterochemistry of the highly mutagenic 7,8-diol 9,10-epoxides derived from the potent carcinogen trans-7,8-dihydroxy-7,8-dihydrobenzol[a]pyrene. J Am Chem Soc. 1977 Mar 30;99(7):2358–2359. doi: 10.1021/ja00449a066. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES