Caenorhabditis elegans generates biologically relevant levels of genotoxic metabolites from aflatoxin B1 but not benzo[a]pyrene in vivo

Maxwell C.K. Leung, Jared V. Goldstone, Windy A. Boyd, Jonathan H. Freedman, Joel N. Meyer

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

There is relatively little information regarding the critical xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in Caenorhabditis elegans, despite this organism's increasing use as a model in toxicology and pharmacology. We carried out experiments to elucidate the capacity of C. elegans to metabolically activate important promutagens via CYPs. Phylogenetic comparisons confirmed an earlier report indicating a lack of CYP1 family enzymes in C. elegans. Exposure to aflatoxin B1 (AFB1), which is metabolized in mammals by CYP1, CYP2, and CYP3 family enzymes, resulted in significant DNA damage in C. elegans. However, exposure to benzo[a]pyrene (BaP), which is metabolized in mammals by CYP1 family enzymes only, produced no detectable damage. To further test whether BaP exposure caused DNA damage, the toxicities of AFB1 and BaP were compared in nucleotide excision repair (NER)-deficient (xpa-1) and NER-proficient (N2) strains of C. elegans. Exposure to AFB1 inhibited growth more in xpa-1 than N2 nematodes, but the growth-inhibitory effects of BaP were indistinguishable in the two strains. Finally, a CYP-nicotinamide adenine dinucleotide phosphate reductase-deficient strain (emb-8) of C. elegans was found to be more resistant to the growth-inhibitory effect of AFB1 exposure than N2, confirming that the AFB1-mediated growth inhibition resulted from CYP-mediated metabolism. Together, these results indicate that C. elegans lacks biologically significant CYP1 family-mediated enzymatic metabolism of xenobiotics. Interestingly, we also found that xpa-1 nematodes were slightly more sensitive to chlorpyrifos than were wild type. Our results highlight the importance of considering differences between xenobiotic metabolism in C. elegans and mammals when using this alternative model in pharmaceutical and toxicological research.

Original languageEnglish (US)
Article numberkfq295
Pages (from-to)444-453
Number of pages10
JournalToxicological Sciences
Volume118
Issue number2
DOIs
StatePublished - Dec 2010

Keywords

  • Aflatoxin B
  • Benzo[a]pyrene
  • Caenorhabditis elegans
  • Cytochrome P450
  • Genotoxicity
  • Nucleotide excision repair

ASJC Scopus subject areas

  • Toxicology

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