Christian Hoffman

Detection of Acrolein Congener-DNA Adducts Isolated from Cellular Systems

α,β-unsatured carbonyl compounds are potential carcinogens present in significant amounts as environmental pollutants, natural products or biological activated metabolites. This laboratory has shown that these compounds exert distinct mutagenic (Ames TA100) and genotoxic (SOS) effects. DNA adduct formation is a possible explanation in the underlying mechanism of these biological processes. Resulting from a structure reactivity study it was shown that the primary covalent binding of these compounds to the DNA bases occurs with 2’ deoxyguanosine 1 resulting in 1,N2 cyclic adducts, 2a,b or 3a,b.

Mutagenicity of methylvinyl ketone in Salmonella typhimurium TA100 — indication for epoxidation as an activation mechanism

This paper shows that MVK is a mutagen for Salmonella typhimurium TA 100 not only in the liquid assay as previously reported, but aslo in the preincubation assay

Risk assessment for mutagenic and carcinogenic activities of α,β-unsaturated carbonyl compounds by a screening strategy based on structure-activity relationships

Abstract α,β-Unsaturated compounds are ubiquitous and are formed endogenously. They form DNA adducts and are a constant source of DNA damage. A speedy screening strategy based on structure-activity relationships and a battery of prescreening tests for a rapid and reliable assessment of the role of these compounds in mutagenesis and carcinogenesis is presented and discussed. In this screening strategy, time-consuming and expensive animal tests are replaced by in vitro test with bacteria and cell cultures. The results of the mutagenicity and genotoxicity tests, as well as the results of the binding studies of α,β-unsaturated carbonyl compounds with DNA components, and the corresponding structure-activity relationships, are presented.

1,N2-cyclic deoxyguanosine adducts and guanine adducts of 2-haloacroleins. Isolation, characterization, isomerization and stability

The reaction of the mutagenic 2-haloacroleins, 2-fluoroacrolein, 2-chloroacrolein and 2-bromoacrolein, with nucleosides and 5′-mononucleotides was studied. We found two different regioisomers of 1,N2-cyclic deoxyguanosine adducts of 2-chloroacrolein and 2-bromoacrolein: type A, the 6-hydroxy, 7-haloadduct in which the OH-substituent is vicinal to the N2-atom of the guanine moiety and type B, the 8-hydroxy, 7-haloadduct in which the OH-group is adjacent to the N1-atom of the guanine moiety. The major adducts were the trans pairs of diastereomers of type A and type B in which the 6,7-substituents as well as the 7,8-substituents are in the energetically favoured diaxial position of the newly formed tetrahydropyrimidine ring. In the case of the type A regioisomers, the cis pairs of diastereomers (traces with chloroacrolein and about 4% with bromoacrolein) were also found in which the halosubstituent probably takes the equatorial position. Due to the anomeric effect, the OH-group takes the axial position in both regioisomers. No cis isomers of the type B regioisomers could be isolated. Acid hydrolysis of the deoxyguanosine adducts released deoxyribose, and the respective guanine adducts were isolated and characterized. Besides the vicinal halo, hydroxy adducts, trace amounts of the corresponding dihydroxy adducts were formed by hydrolysis of the chlorine or bromine substituents. The dihydroxy compounds possess the same structures and conformations in the newly formed tetrahydropyrimidine ring as do the halo, hydroxy adducts. Under our conditions no adducts other than those with deoxyguanosine and guanine could be identified. We found, however, indication for the formation of deoxyadenosine adducts when using dimethylsulfoxide as a solvent. No adducts in substantical amounts could be isolated with fluoroacrolein due to its rapid polymerization.