Bacterial and mammalian cell mutagenicity of four optically active bay-region 10,11-diol-8,9-epoxides of the nitrogen heterocycle dibenz[a,h]acridine.
The mutagenic activities of the enantiomers of the diastereomeric pair of bay-region 10,11-diol-8,9-epoxides of dibenz[a,h]acridine (DB[a,h]ACR) were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strains TA98 and TA100 of S.typhimurium, the (-)-[8S,9R,10R,11S] diol-epoxide was the most mutagenic compound, inducing 1200 and 6900 His+ revertants/nmol respectively. The mutagenic activity of each of the remaining three isomers was essentially independent of the bacterial strain used and had 14-72% of the activity of the [S,R,R,S] isomer. However, in Chinese hamster V79 cells, the (+)-[8R,9S,10S,11R] diol-epoxide was the most mutagenic compound (68 8-azaguanine resistant variants/nmol/10(5) cells), inducing from 2 to 11 times as many mutations as the other three isomers. These results are analogous to previous studies with the bay-region diol-epoxides of other polycyclic hydrocarbons in that the isomer with [R,S,S,R] absolute configuration has had variable activity in the bacterial assays, but has generally been the most active in the mammalian cells. Furthermore, this isomer has almost always been highly tumorigenic in the mouse.
Chang
R L
RL
Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855.
Battista
S
S
Wong
C Q
CQ
Kumar
S
S
Kole
P L
PL
Sikka
H C
HC
Balani
S K
SK
Jerina
D M
DM
Conney
A H
AH
Wood
A W
AW
D000166:Acridines / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000166:Acridines; D004852:Epoxy Compounds; D009153:Mutagens