Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene

• Published in: Carcinogenesis (New York) 2013-09, Vol.34 (9), p.2184-2191
• Main Authors: Chang, Richard L, Wood, Alexander W, Huang, Mou Tuan, Xie, Jian Guo, Cui, Xiao Xing, Reuhl, Kenneth R, Boyd, D R, Lin, Yong, Shih, Weichung Joe, Balani, Suresh K, Yagi, Haruhiko, Jerina, Donald M, Conney, Allan H
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenesis - chemically induced; Carcinogenesis - chemistry; Carcinogenesis - pathology; Chrysenes - chemistry; Chrysenes - pharmacology; Chrysenes - toxicity; Cricetinae; Epoxy Compounds - pharmacology; Epoxy Compounds - toxicity; Humans; Mice; Mutagenesis - drug effects; Mutagens - pharmacology; Mutagens - toxicity; Original Manuscript; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; Skin Neoplasms - chemically induced; Skin Neoplasms - pathology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt164

Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3β,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3α,4β-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.