A model of sensitivity: 1,3-butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene.
The specific role that polymorphisms in xenobiotic metabolizing enzymes play in modulating sensitivity to 1,3-butadiene (BD) genotoxicity has been relatively unexplored. The enzyme microsomal epoxide hydrolase (mEH) is important in detoxifying the mutagenic epoxides of BD (butadiene monoepoxide [BDO], butadiene diepoxide [BDO(2)]). Polymorphisms in the human mEH gene appear to affect the function of the enzyme. We exposed mice with normal mEH activity (WT) and knockout mice without mEH activity (KO) to 20 ppm BD (inhalation) or 30 mg/kg BDO(2) (intraperitoneal [IP] injection). We then compared Hprt mutant frequencies (MFs) among these groups. KO mice exposed to BD exhibited a significant (P < 0.05) 12.4-fold increase in MF over controls and a significant 5.4-fold increase in MF over exposed WT mice. Additionally, KO mice exposed to BDO(2) exhibited a significant 4.5-fold increase in MF over controls and a significant 1.7-fold increase in MF over exposed WT mice. We also compared genomic damage in WT and KO mice (comet tail moment) following IP exposure to 3 mg/kg and 30 mg/kg BDO(2). KO mice exposed to 3 mg/kg exhibited significantly more DNA damage than controls (7.5-12.1-fold increase) and exposed WT mice (3 mg/kg; 4.8-fold increase). KO mice exposed to 30 mg/kg BDO(2) exhibited significantly more DNA damage than all other groups (2.3-27.9-fold increase). Correlation analysis indicated that a significant, positive relationship (r(2) = 0.92) exists between comet-measured damage and Hprt MFs. The lack of mEH activity increases the genetic sensitivity of mice exposed to BD and BDO(2). This model should facilitate a mechanistic understanding of the observed variation in human genetic sensitivity following exposure to BD.
Wickliffe
Jeffrey K
JK
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas 77555, USA. jkwickli@utmb.edu
Ammenheuser
Marinel M
MM
Salazar
James J
JJ
Abdel-Rahman
Sherif Z
SZ
Hastings-Smith
Darlene A
DA
Postlethwait
Edward M
EM
Lloyd
R Stephen
RS
Ward
Jonathan B
JB
D000280:Administration, Inhalation; D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D004852:Epoxy Compounds / Q000633:toxicity*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007274:Injections, Intraperitoneal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000187:drug effects
D002070:Butadienes; D004852:Epoxy Compounds; C007366:diepoxybutane; D007041:Hypoxanthine Phosphoribosyltransferase; D004851:Epoxide Hydrolases; C031763:1,3-butadiene