The infusion or decoction of its root bark has widespread use in folk medicine. In all cases, the peak at m/z 237, assigned to the stabilized electrophilic oxybenzopyranyl species which results from the loss of the sulphur or oxygen substituent at C(4), was present.Finally, the incubation of racemic epoxide (1) with rat liver cytosolic fraction, followed by enzymatic degradation and further thermospray HPLC/MS analysis of the resulting methylated cysteine derivatives, allowed the identification, for the first time in a biological matrix, of the pairs of cis and trans glutathione conjugates (3a).īACKGROUND: The root powder of Periploca laevigata is used for preparing soft drinks and as an aromatic in Tunisia.
Likewise, 3,4-dihydrodiols (2) also afforded satisfactory responses. Thus, whereas standards of the glutathione adducts 3a afforded poor responses, the corresponding cysteine (3b) and N-acetylcysteine (3c) derivatives gave defined spectral patterns and good sensitivity levels, particularly when analysed as methyl esters. Thermospray high-performance liquid chromatography/mass spectrometry (HPLC/MS) in the positive ion mode has proven to be a useful technique for analysing different synthetic models of potential metabolites of 3,4-epoxyprecocene II (1), the postulated bioactive epoxide responsible for the cytotoxic activity exhibited by precocenes on a variety of insect and mammal tissues.
Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1-(2-hydroxy-3,4-epoxybut-1-yl)-adenine adducts, which undergo an SN2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. We found that synthetic N6-(2-hydroxy-3,4-epoxybut-1-yl)-2′-deoxyadenosine (compound 1) representing the product of N6-adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of organic base. The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB: N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (compound 2), 1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (compound 3), and 1,N6-(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2′-deoxyadenosine (compound 4). Although it preferentially modifies guanine within DNA, DEB induces a large number of A → T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. 1,2,3,4-Diepoxybutane (DEB)1 is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air.
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