title: Dose-dependent differences in the mutational profiles of (-)-(1R,2S,3S,4R)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and its less carcinogenic enantiomer.
abstract: Chinese hamster V-79 cells were treated with high cytotoxic or low noncytotoxic concentrations of the highly carcinogenic and mutagenic (-)-(1R,2S,3S,4R)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [(-)-B[c]PhDE; fjord-region diol epoxide] or its biologically less active (+)-(1S,2R,3R,4S) enantiomer [(+)-B[c]PhDE]. The benzylic 4-hydroxyl group and the epoxide oxygen are trans in both enantiomers. Independent 8-azaguanine-resistant clones were isolated. The coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene was amplified by reverse transcription-PCR and sequenced. For (-)-B[c]PhDE, mutation frequencies were 10- or 356-fold above background for the low (0.01-0.1 microM; 97% cell survival) or high (1.0-1.25 microM; 26% cell survival) doses, respectively. For the high dose group, 20 of 64 base substitutions occurred at GC base pairs (31%) and 44 at AT base pairs (69%). For the low-dose group, 6 of 55 base substitutions were at GC base pairs (11%), and 49 were at AT base pairs (89%). For the less active (+)-B[c]PhDE, mutation frequencies were 17- or 372-fold above background for the low (0.12-0.5 microM; 95% cell survival) or high (2.0-3.0 microM; 31% cell survival) doses, respectively. In contrast to the results with the (-)-B[c]PhDE, both the high- and the low-dose groups for (+)-B[c]PhDE gave a 50:50 distribution of base substitution at GC versus AT base pairs. Our data indicate that: (a) transversions were the predominant base substitutions observed for both the (+)- and (-)-enantiomers of B[c]PhDE; (b) (-)-B[c]PhDE showed high selectivity for causing AT --> TA transversions, whereas considerably less selectivity was observed for (+)-B[c]PhDE; (c) (-)-B[c]PhDE had a different hot spot profile for base substitutions than did (+)-B[c]PhDE, but some common hot spots were observed for both compounds; and (d) decreasing the dose of (-)-B[c]PhDE increased the proportion of mutations at AT base pairs and decreased those at GC base pairs, but this was not observed for (+)-B[c]PhDE.
authors.affiliation: Department of Chemical Biology, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wei
authors.forename: R L
authors.initials: RL
authors.lastname: Chang
authors.forename: X X
authors.initials: XX
authors.lastname: Cui
authors.forename: K A
authors.initials: KA
authors.lastname: Merkler
authors.forename: C Q
authors.initials: CQ
authors.lastname: Wong
authors.forename: H
authors.initials: H
authors.lastname: Yagi
authors.forename: D M
authors.initials: DM
authors.lastname: Jerina
authors.forename: A H
authors.initials: AH
authors.lastname: Conney
mesh_terms: D000818:Animals; D001483:Base Sequence; D006224:Cricetinae; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005091:Exons; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity*; D010616:Phenanthrenes / Q000633:toxicity*; D013237:Stereoisomerism
chemical_list: D018736:DNA Adducts; D009153:Mutagens; D010616:Phenanthrenes; C090203:1,2-epoxy-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene; D007041:Hypoxanthine Phosphoribosyltransferase