Mutagenic specificity of a potent carcinogen, benzo(c)phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide, which reacts with adenine and guanine in DNA

Journal Article · Sat Apr 01 04:00:00 EST 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.86.7.2291· OSTI ID:5349243

Bigger, C A.H.; Strandberg, J; Yagi, H; Jerina, D M; Dipple, A ^[1]

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1. Bionetics Research, Inc., Frederick, MD (USA)

Mutations were induced in the supF gene of the pS189 shuttle vector by treatment with optically active benzo(c)phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide in vitro and replication in human cells. The induced mutation frequency was 60-fold greater than the spontaneous rate, and most of the mutations analyzed were transversions (86%), which principally consisted of similar numbers of A{center dot}T {yields} T{center dot}A and G{center dot}C {yields} T{center dot}A changes. The unusual susceptibility of A{center dot}T pairs to mutation by this chemical agent is consistent with its chemical reactivity toward adenine and argues that the mutations are targeted to the adducts formed. The central base in the sequences 5{prime}-AGA-3{prime}, 5{prime}-AAC-3{prime}, and 5{prime}-GAG-3{prime} was particularly susceptible to mutation. Twelve hot spots in the supF gene accounted for most mutations seen. Some of these hot spots differed from those found by others for racemic benzo(a)pyrene dihydrodiol epoxide and, even when a hotspot was common, the mutagenic changes were not always the same. Although adenine insertion opposite a noninstructional lesion could account for most of the data, no single mutagenic mechanism could encompass all of it. The cellular machinery that converts chemical damage to mutations must determine the mutational result to a large extent, but the findings herein show that the chemical agent itself plays a large role in determining both the location and the nature of the mutations that arise.

• OSTI ID: 5349243
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 86:7; ISSN 0027-8424; ISSN PNASA
• 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.
ADENINES
AMINES
ANIMALS
ANTIMETABOLITES
AROMATICS
AZAARENES
BIOLOGICAL EFFECTS
CARCINOGENESIS
DNA
DNA BASE TRANSITIONS
DRUGS
EPOXIDES
GENETIC EFFECTS
GUANINE
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
HYDROXY COMPOUNDS
MAMMALS
MAN
MOLECULAR BIOLOGY
MUTATIONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PATHOGENESIS
POLYCYCLIC AROMATIC HYDROCARBONS
PRIMATES
PURINES
SPONTANEOUS MUTATIONS
VERTEBRATES