Mutagenicity of nitro- and amino-substituted carbazoles in Salmonella typhimurium. III. Methylated derivatives of 9H-carbazole.
The mutagenic potency of nine methylnitrocarbazoles, four methylaminocarbazoles and the methylcarbazole parent compounds was evaluated in Salmonella typhimurium TA98 and TA100, in the absence and presence of S9 isolated from Aroclor-induced rat liver. Nitro derivatives were additionally tested in TA98NR and TA98/1,8DNP6, and mutagenicity of nitrocarbazoles bearing methyl groups in positions 1 and 4 was also determined in TA1537 and TA1977, with and without S9. The addition of methyl groups on non-mutagenic carbazole can induce a mutagenic response where the intensity and nature of the effect depends on the position of the substitution: base-pair substitutions were only observed for N-methylated carbazoles, whereas 1,4-dimethylated compounds exhibited frameshift mutagenicity. All these activities depended on the presence of S9. From its dependence on classical nitroreductases, direct mutagenicity of methylnitro derivatives should be attributed to bacterial reduction of nitro groups. The influence of the methyl groups (and other additional substituents) on mutagenicity of these derivatives is discussed through their effects on life-time and reactivity of the intermediates (i.e., hydroxylamines and nitrenium ions), taking into account the nature, the position and the number of substituted sites Mutagenic activity of methylnitrocarbazoles was also tentatively correlated with various molecular descriptors. Among them hydrophobicity was found to be strongly correlated with the mutagenicity of the 1,4diMe3NC isomers. On the other hand, mutagenic potency of the nitrated and aminated methylcarbazoles varied independently of parameters linked to their oxidoreduction properties (i.e., reduction and oxidation potentials, LUMO and HOMO energies).
André
V
V
Laboratoire de Cancérologie Expérimentale, Centre F. Baclesse, Caen, France.
Boissart
C
C
Sichel
F
F
Gauduchon
P
P
Le Talaër
J Y
JY
Lancelot
J C
JC
Mercier
C
C
Chemtob
S
S
Raoult
E
E
Tallec
A
A
D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
D000588:Amines; D002227:Carbazoles; D009153:Mutagens; D009574:Nitro Compounds