Mutagenicity of dihydrodiols and diol epoxides of dibenz[a, h]acridine in bacterial and mammalian cells.
Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz[a, h]acridine can form two diastereomeric pairs of these diol epoxides which are not positionally equivalent as a result of the nitrogen atom at position 7. We have assessed the structure-activity relationships resulting from heterocyclic nitrogen substitution by examining the mutagenic activity of these four bay-region diol epoxides of dibenz[a,h]acridine in both bacterial and mammalian cells. In strains TA98 and TA100 of Salmonella typhimurium, the diastereomeric 10,11-diol-8,9-epoxides were 20 to 40 times more mutagenic than the corresponding 3,4-diol-1,2-epoxides. Furthermore, in strain TA100, dibenz[a,h]acridine 10,11-dihydrodiol, the expected metabolic precursor of the 10,11-diol-8,9-epoxide, was metabolically activated by rat hepatic microsomes up to a 12-fold greater extent than the 3,4-dihydrodiol. In Chinese hamster V79 cells, the 10,11-diol-8,9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3,4-diol-1,2-epoxide counterparts. Quantum mechanical calculations of the predicted ease of benzylic carbocation formation at C-1 and C-8 from the diol epoxides indicate that the 3,4-diol-1,2-epoxides should be less reactive due to resonance destabilization of the C-1 carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3,4-diol-1,2-epoxides may explain their decreased mutagenic activity.
Wood
A W
AW
Roche Reserch Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Chang
R L
RL
Katz
M
M
Conney
A H
AH
Jerina
D M
DM
Sikka
H C
HC
Levin
W
W
Kumar
S
S
D000166:Acridines / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D003412:Cricetulus; D004852:Epoxy Compounds / Q000633:toxicity*; D004988:Ethers, Cyclic / Q000633:toxicity*; D005798:Genes, Bacterial; D009152:Mutagenicity Tests; D009153:Mutagens; D012486:Salmonella typhimurium / Q000235:genetics*
D000166:Acridines; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D009153:Mutagens; C022289:dibenzacridine