Detoxification of olefinic epoxides and nucleotide excision repair of epoxide-mediated DNA damage: Insights from animal models examining human sensitivity to 1,3-butadiene.
1,3-Butadiene (BD) is a well-documented mutagen and carcinogen in rodents and is currently classified as a probable carcinogen in humans. Studies investigating workers exposed to BD indicate that, in some plants, there may be an increased genetic risk, and that polymorphisms in biotransformation and DNA repair proteins may modulate genetic susceptibility. To investigate the role of genetic polymorphisms in microsomal epoxide hydrolase (mEH) or nucleotide excision repair (NER) in contributing to the mutagenicity of BD, we conducted a series of experiments in which mice lacking mEH or NER activity were exposed to BD by inhalation or to the reactive epoxide metabolites of BD (epoxybutene-EB or diepoxybutane-DEB) by i.p. injection. Genetic susceptibility was measured using the Hprt cloning assay. Both deficient strains of mouse were significantly more sensitive to the mutagenic effects of BD and the injected epoxides. These studies provide support for the critical role that mEH plays in the biotransformation of BD, and the role that NER plays in maintaining genomic integrity following exposure to BD. Additional studies are needed to examine the importance of base excision repair (BER) in maintaining genomic integrity, the differential formation of DNA and protein adducts in deficient strains, and the potential for enhanced sensitivity to BD genotoxicity in mice either lacking or deficient in both biotransformation and DNA repair activity.
Wickliffe
Jeffrey K
JK
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX 77555, USA. jeff.wickliffe@utmb.edu
Herring
Stacy M
SM
Hallberg
Lance M
LM
Galbert
Lori A
LA
Masters
Oscar E
OE
Ammenheuser
Marinel M
MM
Xie
Jingwu
J
Friedberg
Errol C
EC
Lloyd
R Stephen
RS
Abdel-Rahman
Sherif Z
SZ
Ward
Jonathan B
JB
D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004851:Epoxide Hydrolases / Q000172:deficiency; D004852:Epoxy Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008658:Inactivation, Metabolic; D019570:Inhalation Exposure; D007274:Injections, Intraperitoneal; D051379:Mice; D023421:Models, Animal; D009154:Mutation / Q000235:genetics
D002070:Butadienes; D004852:Epoxy Compounds; C007366:diepoxybutane; D007041:Hypoxanthine Phosphoribosyltransferase; D004851:Epoxide Hydrolases; C031763:1,3-butadiene