Reaction of epichlorohydrin with adenosine, 2′-deoxyadenosine and calf thymus DNA: Identification of adducts

Quantification of N-(3-chloro-2-hydroxypropyl)valine in human haemoglobin as a biomarker of epichlorohydrin exposure by gas chromatography–tandem mass spectrometry with stable-isotope dilution☆

“…We therefore think that careful sample handling during the whole work-up procedure is a crucial aspect of the method. This view is supported by many recent reports on the determination of 3-chloro-2-hydroxypropyl adducts of ECH to DNA bases and amino acids [16][17][18][19][20][21][22]. Thus, the hydrolysis of the chlorine-carrying methylene group at C-3 does not seem to be an immanent, but a work-up dependent problem.…”

“…In recent years, the search for appropriate biomarkers of ECH exposure has focused on adducts to macromolecules in blood such as haemoglobin [14,15] and lymphocyte or calf thymus DNA [16][17][18][19][20], or on conjugates in urine such as mercapturic acids [21,22]. In most studies, with the exception of Hindsø Landin et al [14], the 3-chloro-2-hydroxypropyl type adducts or GSH conjugates have been preferred over the analysis of 2,3-dihydroxypropyl adducts due to the higher specificity of these adducts with regard to ECH, because the characteristic chlorine atom of ECH is still present in the adduct.…”

Effect of O6‐alkylguanine‐DNA alkyltransferase on genotoxicity of epihalohydrins

“…In vitro analyses have demonstrated the formation of epihalohydrin induced DNA adducts at nitrogen atoms of guanine and adenine bases (Singh et al, 1996; Sund and Kronberg, 2006; Romano et al, 2007). In the absence of any significant number of mutations in EBH-treated cells without AGT we cannot definitively assign the mutations seen in the empty vector expressing TRG8 cells to EBH.…”

“…The most prevalent adduct is at the N 7-position of guanine because of the nucleophilicity and steric availability of that position (Kolman et al, 2002). However, evidence does exist for alkylation of DNA at alternative sites, mainly the N 1 and N 3-positions of adenine and the N 3-position of cytosine (Sund and Kronberg, 2006). Due to their instability, several of these adducts undergo chemical transformation yielding secondary DNA damage, which could likely be responsible for some of the genotoxicity seen with these compounds in cell culture (Qian and Dipple, 1995; Koskinen and Plna, 2000; Plna et al, 2000).…”

Quantitative PCR analysis of diepoxybutane and epihalohydrin damage to nuclear versus mitochondrial DNA

“…Furthermore, the lower GC content of mtDNA has been suggested to account for DEB’s preferential damage to nDNA in yeast cells [61]. However, our loci do not significantly differ in their GC content (Table 4), although GC content does not entirely reflect abundance of target sites because of minor reactions with adenine in vivo by these agents [13, 17, 62, 63]. Nonetheless, DEB cross-linking is more specific than that of the epihalohydrins [21], making it unlikely that the latter compounds would find fewer targets in the mitochondrial genome than in the nucleus given that DEB lesions are comparable for the two genomes.…”