title: Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene.
abstract: 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.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Chang
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wood
authors.forename: Mou Tuan
authors.initials: MT
authors.lastname: Huang
authors.forename: Jian Guo
authors.initials: JG
authors.lastname: Xie
authors.forename: Xiao Xing
authors.initials: XX
authors.lastname: Cui
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.forename: D R
authors.initials: DR
authors.lastname: Boyd
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yagi
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jerina
authors.forename: Allan H
authors.initials: AH
authors.lastname: Conney
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000737:chemistry / Q000473:pathology*; D002911:Chrysenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006224:Cricetinae; D004852:Epoxy Compounds / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002911:Chrysenes; D004852:Epoxy Compounds; D009153:Mutagens; C021977:chrysene,2-diol-3,4-epoxide-1