Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites

Y. Yang, W. J. Griffiths, M. Nordling, J. Nygren, L. Möller, J. Bergman, E. Liepinsh, G. Otting, J. A. Gustafsson, J. Rafter, J. Sjövall

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The metabolism of benzo[a]pyrene (BP) is known to lead to a large number of oxygenated compounds, some of which can bind covalently to DNA. We have studied the integrated metabolism of BP in vivo in germ-free rats given 14C-labeled BP. Urinary metabolites were separated into groups according to acidity using lipophilic ion exchangers. The groups were analyzed by mass spectrometry and were further fractionated by high-performance liquid chromatography. The fraction of urinary metabolites previously shown to contain N-acetylcysteine and glucuronic acid conjugates was found to contain derivatives of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid as major components. These compounds, which were identified by mass spectrometry and NMR, accounted for about 30% of the total metabolites in urine, demonstrating that, surprisingly, ring opening is a major pathway for metabolism of BP in the germ-free rat. The dicarboxylic acid may be excreted in urine as an ester glucuronide. By using the single cell gel electrophoresis or COMET assay, we were able to demonstrate that the anhydride of 7-oxo-benz-[d]anthracene-3,4-dicarboxylic acid was an efficient inducer of DNA damage. Taken together, these results indicate that the novel ring opening metabolic pathway may provide alternative mechanisms for the toxicity of BP.

Original languageEnglish (US)
Pages (from-to)15585-15591
Number of pages7
JournalBiochemistry
Volume39
Issue number50
DOIs
StatePublished - Dec 19 2000

ASJC Scopus subject areas

  • Biochemistry

Fingerprint

Dive into the research topics of 'Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites'. Together they form a unique fingerprint.

Cite this