Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1983 Nov 15;216(2):377–384. doi: 10.1042/bj2160377

Regio- and stereo-selective metabolism of 4-methylbenz[a]anthracene by the fungus Cunninghamella elegans.

C E Cerniglia, P P Fu, S K Yang
PMCID: PMC1152514  PMID: 6661203

Abstract

Metabolism of 4-methylbenz[a]anthracene by the fungus Cunninghamella elegans was studied. C. elegans metabolized 4-methylbenz[a]anthracene primarily at the methyl group, this being followed by further metabolism at the 8,9- and 10,11-positions to form trans-8,9-dihydro-8,9-dihydroxy-4-hydroxymethylbenz[a]anthracene and trans-10,11-dihydro-10,11-dihydroxy-4-hydroxymethylbenz[a]anthracene. There was no detectable trans-dihydrodiol formed at the methyl-substituted double bond (3,4-positions) or at the 'K' region (5,6-positions). The metabolites were isolated by reversed-phase high-pressure liquid chromatography and characterized by the application of u.v.-visible-absorption-, 1H-n.m.r.- and mass-spectral techniques. The 4-hydroxymethylbenz[a]anthracene trans-8,9- and -10,11-dihydrodiols were optically active. Comparison of the c.d. spectra of the trans-dihydrodiols formed from 4-methylbenz[a]anthracene by C. elegans with those of the corresponding benz[a]anthracene trans-dihydrodiols formed by rat liver microsomal fraction indicated that the major enantiomers of the 4-hydroxymethylbenz[a]anthracene trans-8,9-dihydrodiol and trans- 10,11-dihydrodiol formed by C. elegans have S,S absolute stereochemistries, which are opposite to those of the predominantly 8R,9R- and 10R,11R-dihydrodiols formed by the microsomal fraction. Incubation of C. elegans with 4-methylbenz[a]anthracene under 18O2 and subsequent mass-spectral analysis of the metabolites indicated that hydroxylation of the methyl group and the formation of trans-dihydrodiols are catalysed by cytochrome P-450 mono-oxygenase and epoxide hydrolase enzyme systems. The results indicate that the fungal mono-oxygenase-epoxide hydrolase enzyme systems are highly stereo- and regio-selective in the metabolism of 4-methylbenz[a]anthracene.

Full text

PDF
377

Selected References

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

  1. Cerniglia C. E., Althaus J. R., Evans F. E., Freeman J. P., Mitchum R. K., Yang S. K. Stereochemistry and evidence for an arene oxide-NIH shift pathway in the fungal metabolism of naphthalene. Chem Biol Interact. 1983 Apr-May;44(1-2):119–132. doi: 10.1016/0009-2797(83)90134-5. [DOI] [PubMed] [Google Scholar]
  2. Cerniglia C. E., Fu P. P., Yang S. K. Metabolism of 7-methylbenz[a]anthracene and 7-hydroxymethylbenz[a]anthracene by Cunninghamella elegans. Appl Environ Microbiol. 1982 Sep;44(3):682–689. doi: 10.1128/aem.44.3.682-689.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hanzlik R. P., Edelman M., Michaely W. J., Scott G. Enzymatic hydration of (18O)epoxides. Role of nucleophilic mechanisms. J Am Chem Soc. 1976 Mar 31;98(7):1952–1955. doi: 10.1021/ja00423a050. [DOI] [PubMed] [Google Scholar]
  4. Lu A. Y., Miwa G. T. Molecular properties and biological functions of microsomal epoxide hydrase. Annu Rev Pharmacol Toxicol. 1980;20:513–531. doi: 10.1146/annurev.pa.20.040180.002501. [DOI] [PubMed] [Google Scholar]
  5. Malaveille C., Tierney B., Grover P. L., Sims P., Bartsch H. High microsome-mediated mutagenicity of the 3,4-dihydrodiol of 7-methylbenz[a]anthracene in S. typhimurium TA 98. Biochem Biophys Res Commun. 1977 Mar 21;75(2):427–433. doi: 10.1016/0006-291x(77)91060-9. [DOI] [PubMed] [Google Scholar]
  6. Stevenson J. L., Von Haam E. Carcinogenicity of benzo(a) anthracene and benz(c)phenanthrene derivatives. Am Ind Hyg Assoc J. 1965 Sep-Oct;26(5):475–478. doi: 10.1080/00028896509342760. [DOI] [PubMed] [Google Scholar]
  7. Thakker D. R., Levin W., Yagi H., Turujman S., Kapadia D., Conney A. H., Jerina D. M. Absolute stereochemistry of the trans-dihydrodiols formed from benzo[a]anthracene by liver microsomes. Chem Biol Interact. 1979 Oct;27(2-3):145–161. doi: 10.1016/0009-2797(79)90122-4. [DOI] [PubMed] [Google Scholar]
  8. Wislocki P. G., Fiorentini K. M., Fu P. P., Yang S. K., Lu A. Y. Tumor-initiating ability of the twelve monomethylbenz[a]anthracenes. Carcinogenesis. 1982;3(2):215–217. doi: 10.1093/carcin/3.2.215. [DOI] [PubMed] [Google Scholar]
  9. Wislocki P. G., Juliana M. M., MacDonald J. S., Chou M. W., Yang S. K., Lu A. Y. Tumorigenicity of 7,12-dimethylbenz[a]anthracene, its hydroxymethylated derivatives and selected dihydrodiols in the newborn mouse. Carcinogenesis. 1981;2(6):511–514. doi: 10.1093/carcin/2.6.511. [DOI] [PubMed] [Google Scholar]
  10. Wu J., Wong L. K. Microbial transformations of 7,2-dimethylbenz[a]anthracene. Appl Environ Microbiol. 1981 Mar;41(3):843–845. doi: 10.1128/aem.41.3.843-845.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Yang S. K., Chou M. W., Fu P. P., Wislocki P. G., Lu A. H. Epoxidation reactions catalyzed by rat liver cytochromes P-450 and P-448 occur at different faces of the 8,9-double bond of 8-methylbenz[a]anthracene. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6802–6806. doi: 10.1073/pnas.79.22.6802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Yang S. K. The absolute stereochemistry of the major trans-dihydrodiol enantiomers formed from 11-methylbenz[a]anthracene by rat liver microsomes. Drug Metab Dispos. 1982 May-Jun;10(3):205–211. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES