Implication of nitro group reduction in the mutagenic and chromosome damaging activities of 22 new 5-nitroisoquinolines by the Salmonella mutagenicity test and the cytokinesis-blocked micronucleus assay.
The mutagenic (MUT) and chromosome-damaging (CHR) activities of 22 potential antimalarial drugs (5-nitroisoquinoline derivatives) were evaluated by the Salmonella test and the cytokinesis-blocked micronucleus assay (CBMN). The Salmonella mutagenicity test was performed with and without metabolic activation (S9 mix) in S. typhimurium strains TA100 and YG1042 (an overproducing nitroreductase and O-acetyltransferase TA100 strain). The CBMN was carried out on human lymphocytes without metabolic activation. Four concentrations were tested: 1, 10, 100 and 1000 ng/ml. MUT was expressed as minimal mutagenic concentrations (MMC, microM) and CHR was expressed as minimal chromosome-damaging concentrations (MCDC, nM) to compare both activities. All the 5-nitroisoquinoline compounds were mutagenic in TA100. MMC ranged from 0.1 to 52.9 microM in TA100. A statistically significant decrease in MMC was observed in YG1042 (8 x 10(-3) to 3.5 microM), implicating reduction of the nitro group. Modulation of MUT by S9 mix was not significant in TA100 and YG1042. CHR was detected in 13 products for at least one concentration. Among the chromosome-damaging compounds, the MCDC ranged from 2.9 x 10(-3) to 3.6 nM. No relationship was found between MUT and CHR, suggesting two distinct pathways of DNA damage.
Orsière
T
T
Laboratoire de Biogénotoxicologie et Mutagenèse Environnementale (EA 1784), Faculté de Médecine et de Pharmacie, Université de la Méditerranée, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France.
De Méo
M
M
Rathelot
P
P
Pompili
J
J
Galas
M
M
Castegnaro
M
M
Vanelle
P
P
Duménil
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D015162:Micronucleus Tests; D008875:Middle Aged; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009574:Nitro Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D019163:Reducing Agents; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins / Q000187:drug effects / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D007546:Isoquinolines; D009153:Mutagens; D009574:Nitro Compounds; D019163:Reducing Agents; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins