DNA-glutathione adducts derived from vic-dihaloalkanes: mechanisms of mutagenesis.
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.
Guengerich
F P
FP
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Humphreys
W G
WG
Kim
D H
DH
Oida
T
T
Cmarik
J L
JL
D000478:Alkylation; D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015946:Ethylene Dibromide / Q000494:pharmacology*; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012486:Salmonella typhimurium
D000969:Antinematodal Agents; D015946:Ethylene Dibromide; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; D005978:Glutathione; D011407:Propane