Comparison of the DNA-alkylating properties and mutagenic responses of a series of S-(2-haloethyl)-substituted cysteine and glutathione derivatives

Journal Article · Thu Nov 01 04:00:00 EST 1990 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00497a008· OSTI ID:5524566

Humphreys, W G; Kim, Dong-Hyun; Cmarik, J L; Shimada, Tsutomu; Guengerich, F P ^[1]

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1. Vanderbilt Univ. School of Medicine, Nashville, TN (USA)

The mutagenicity of 1,2-dibromoethane is highly dependent upon its conjugation to glutathione by the enzyme glutathione S-transferase. The conjugates thus formed can react with DNA and yield almost exclusively N{sup 7}-guanyl adducts. The authors have synthesized the S-haloethyl conjugates of cysteine and glutathione, as well as selected methyl ester and N-acetyl derivatives, and compared them for ability to produce N{sup 7}-guanyl adducts with calf thymus DNA. The cysteine compounds were found to be more reactive toward calf thymus DNA and yielded higher adduct levels than did the glutathione compounds. Adduct levels tended to be suppressed when there was a net charge on the compound and were not affected by substitution of bromine for chlorine, as expected for a mechanism known to involve an intermediate episulfonium ion. Sequence-selective alkylation of fragments of pBR322 DNA was investigated. The ratio of mutations to adducts varied at least 14-fold among the various N{sup 7}-guanyl adducts examined. The results indicate that (1) N{sup 7}-alkylguanine residues can be quite mutagenic and (2) small differences in the structures of a single such adduct can dramatically alter mutagenicity.

• OSTI ID: 5524566
• Journal Information: Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 29:45; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ALKYLATING AGENTS
ALKYLATION
AMINO ACIDS
BACTERIA
BIOLOGICAL EFFECTS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
CYSTEINE
DERIVATIZATION
DNA
DNA ADDUCTS
DRUGS
ENZYMES
GENETIC EFFECTS
GLUTATHIONE
MICROORGANISMS
MUTAGENESIS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
SALMONELLA
SALMONELLA TYPHIMURIUM
THIOLS
TRANSFERASES