The effect of vitamin B 12 on DNA adduction by styrene oxide, a genotoxic xenobiotic.

Vitamin B ₁₂ (cyano- or hydroxo-cobalamin) acts, via its coenzymes, methyl- and adenosyl-cobalamin, as a partner for enzymatic reactions in humans catalysed by methionine synthase and methylmalonyl-CoA mutase. As well as its association with pernicious anaemia, human B ₁₂ deficiency may also be a risk factor for neurological illnesses, heart disease and cancer. In the present work the effect of vitamin B ₁₂ (hydroxocobalamin) on the formation of DNA adducts by the epoxide phenyloxirane (styrene oxide), a genotoxic metabolite of phenylethene (styrene), has been studied using an in vitro model system. Styrene was converted to its major metabolite styrene oxide as a mixture of enantiomers using a microsomal fraction from the livers of Sprague-Dawley rats with concomitant inhibition of epoxide hydrolase. However, microsomal oxidation of styrene in the presence of vitamin B ₁₂ gave diastereoisomeric 2-hydroxy-2-phenylcobalamins. The quantitative formation of styrene oxide-DNA adducts was investigated using 2-deoxyguanosine or calf thymus DNA in the presence or absence of vitamin B ₁₂ . Microsomal incubations containing either deoxyguanosine or DNA in the absence of vitamin B ₁₂ gave 2-amino-7-(2-hydroxy-1-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-1-phenylethyl)-guanine], and 2-amino-7-(2-hydroxy-2-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-2-phenylethyl)guanine] as the principal adducts. With deoxyguanosine the level of formation of guanine adducts was ca. 150 adducts/10 ⁶ unmodified nucleoside. With DNA the adduct level was 36 pmol/mg DNA (ca. 1 adduct/0.83 × 10 ⁵ nucleotides). Styrene oxide adducts from deoxyguanosine or DNA were not detected in microsomal incubations of styrene in the presence of vitamin B ₁₂ . These results suggest that vitamin B ₁₂ could protect DNA against genotoxicity due to styrene oxide and other xenobiotic metabolites. However, this potential defence mechanism requires that the 2-hydroxyalkylcobalamins derived from epoxides are not 'anti-vitamins' and ideally liberate, and therefore, recycle vitamin B ₁₂ . Otherwise, depletion of vitamin B ₁₂ leading to human deficiency could increase the risk of carcinogenesis initiated by genotoxic epoxides.
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