Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests.
3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the (32)P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts.
Reddy
M Vijayaraj
MV
Department of Genetic and Cellular Toxicology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. vijay_reddy@merck.com
Storer
Richard D
RD
Laws
George M
GM
Armstrong
Michael J
MJ
Barnum
John E
JE
Gara
Jennifer P
JP
McKnight
Crystal G
CG
Skopek
Thomas R
TR
Sina
Joseph F
JF
DeLuca
John G
JG
Galloway
Sheila M
SM
D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects* / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000633:toxicity*; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D051381:Rats
D018736:DNA Adducts; D004277:DNA, Single-Stranded; D007211:Indoles; D009153:Mutagens