Abstract
18 Carcinogens, including aflatoxin B(1), benzo(a)pyrene, acetylaminofluorene, benzidine, and dimethylamino-trans-stilbene, are shown to be activated by liver homogenates to form potent frameshift mutagens. We believe that these carcinogens have in common a ring system sufficiently planar for a stacking interaction with DNA base pairs and a part of the molecule capable of being metabolized to a reactive group: these structural features are discussed in terms of the theory of frameshift mutagenesis. We propose that these carcinogens, and many others that are mutagens, cause cancer by somatic mutation. A simple, inexpensive, and extremely sensitive test for detection of carcinogens as mutagens is described. It consists of the use of a rat or human liver homogenate for carcinogen activation (thus supplying mammalian metabolism) and a set of Salmonella histidine mutants for mutagen detection. The homogenate, bacteria, and a TPNH-generating system are all incubated together on a petri plate. With the most active compounds, as little as a few nanograms can be detected.
MeSH Terms
Aflatoxins/pharmacology
Aminopyrine/pharmacology
Animals
Anthracenes/pharmacology
Base Sequence
Benzopyrenes/pharmacology
Biological Assay
Biphenyl Compounds/pharmacology
Carcinogens/pharmacology
DNA, Bacterial
Fluorenes/pharmacology
Humans
Male
Methylcholanthrene/pharmacology
Microsomes, Liver/enzymology
Mutagens/pharmacology
Mutation/drug effects
NADP
Rats
Salmonella typhimurium/drug effects
Stilbenes/pharmacology
Chemicals
Aflatoxins
Anthracenes
Benzopyrenes
Biphenyl Compounds
Carcinogens
DNA, Bacterial
Fluorenes
Mutagens
Stilbenes
Aminopyrine
NADP
Methylcholanthrene
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ames B N
Durston W E
Yamasaki E
Lee F D
References (17)
17 references, click to expand
-
Frameshift mutagenesis in Salmonella.
Cold Spring Harb Symp Quant Biol. 1966;31:221-5
PMID: 4866378
-
Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday.
Cold Spring Harb Symp Quant Biol. 1966;31:77-84
PMID: 5237214
-
The effect of oral phenobarbitone on hepatic microsomal cytochrome P-450 and demethylation activity in rats fed normal and low protein diets.
Biochem Pharmacol. 1969 Jan;18(1):153-7
PMID: 5769345
-
Rapid detection of mutagens and carcinogens.
Cancer Res. 1971 Jul;31(7):970-3
PMID: 4934677
-
A microbial assay for detecting chemical mutagens in tissue homogenates.
Mutat Res. 1971 Jul;12(3):335-7
PMID: 4935357
-
Oxidation and protein binding of aromatic amines by rat liver microsomes.
Chem Biol Interact. 1971 Oct;3(5):321-36
PMID: 5156327
-
Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens.
Science. 1972 Apr 7;176(4030):47-9
PMID: 4551487
-
Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds, and endogenous substrates. II. Role of the cytochrome P-450 and P-448 fractions in drug and steroid hydroxylations.
J Biol Chem. 1972 Mar 25;247(6):1727-34
PMID: 4401153
-
Dimethylnitrosamine: formation of mutagenic compounds by interaction with mouse liver microsomes.
Mutat Res. 1971 Dec;13(4):425-9
PMID: 4401365
-
Molecular basis of a mutational hot spot in the lysozyme gene of bacteriophage T4.
Nature. 1972 Apr 14;236(5346):338-41
PMID: 4553645
-
Antitumor and mutagenic properties of a variety of heterocyclic nitrogen and sulfur mustards.
J Med Chem. 1972 Jul;15(7):739-46
PMID: 4557857
-
Liver microsomal metabolism of aflatoxin B 1 to a reactive derivative toxic to Salmonella typhimurium TA 1530.
Cancer Res. 1972 Oct;32(10):2058-66
PMID: 4404160
-
Carcinogens as frameshift mutagens: metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens.
Proc Natl Acad Sci U S A. 1972 Nov;69(11):3128-32
PMID: 4564203
-
Formation of K-region epoxides as microsomal metabolites of pyrene and benzo(a)pyrene.
Biochem Pharmacol. 1972 Oct 15;21(20):2713-26
PMID: 4647079
-
K-region epoxides of polycyclic hydrocarbons: reactions with nucleic acids and polyribonucleotides.
Biochem Pharmacol. 1973 Mar 15;22(6):661-6
PMID: 4120921
-
An improved bacterial test system for the detection and classification of mutagens and carcinogens.
Proc Natl Acad Sci U S A. 1973 Mar;70(3):782-6
PMID: 4577135
-
Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo.
Biochem J. 1962 Apr;83:114-24
PMID: 14468247