| 2134669 |
Guengerich FP, Humphreys WG, Kim DH, Oida T, Cmarik JL: DNA-glutathione adducts derived from vic-dihaloalkanes: mechanisms of mutagenesis. Princess Takamatsu Symp. 1990;21:101-7.
The conjugation of the prototype dihaloalkane ethylene dibromide (EDB) with glutathione (GSH) yields S-(2-bromoethyl) GSH, which gives rise to S-[2-(N7-guanyl) ethyl] GSH as the major DNA adduct (greater than or equal to 95%). All reaction steps have SN2 character. Another minor DNA and RNA adduct is S-[2-(N1-adenyl) ethyl] GSH, formed in vitro and in vivo. These adducts have similar half-lives in vivo. Enhancement of GSH conjugation or inhibition of cytochrome P-450 IIE1 oxidation enhances DNA adduct levels in vivo and GSH depletion lowers levels. The mercapturic acid N-acetyl-S-[2-(N7-guanyl) ethyl] cysteine is excreted in urine and may find use as a biomarker. A series of compounds of the general structure RSCH2CH2Cl has been used to alkylate Salmonella typhimurium TA100. The ratio of (guanyl) base-pair mutations to N7-guanyl adducts varies dramatically, with S-(2-chloroethyl) GSH apparently producing the most potent guanyl adduct. This mutagenicity is not due to SOS response or alkylation specificity. Physical studies with modified oligonucleotides indicate that the N7-guanyl substitution weakens G-C pairing but does not in itself alter the selectivity of pairing to C in an isolated oligomer. |
1(0,0,0,1) |