Publication Date:
2022-05-26
Description:
Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Toxicological Sciences 118 (2010): 444-453, doi:10.1093/toxsci/kfq295.
Description:
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-deficient (xpa-1) and -
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-NADPH 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.
Description:
This work was supported in part by NIH R21 NS065468 (JNM); the National Toxicology
Program Z01ES102046 (WAB), the Intramural Research Program of the National Institute of
Environmental Health Sciences Z01ES102045 (JHF). JVG was supported by NIH Grants to John
Stegeman (R01-ES015912, and the Superfund Basic Research Program at Boston University 5-
P42-ES007381).
Keywords:
Caenorhabditis elegans
;
Cytochrome P450
;
Aflatoxin B1
;
Benzo[a]pyrene
;
Genotoxicity
;
Nucleotide excision repair
Repository Name:
Woods Hole Open Access Server
Type:
Preprint
Format:
application/pdf
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