TY - JOUR
T1 - Reactions of stereoisomeric and structurally related bay region diol epoxide derivatives of benz[a]anthracene with DNA. Conformations of non-covalent complexes and covalent carcinogen-DNA adducts
AU - Carberry, Susan E.
AU - Shahbaz, Manouchehr
AU - Geacintov, Nicholas E.
AU - Harvey, Ronald G.
N1 - Funding Information:
This work was supported by the U.S. Public Health Service, Grant CA 20851 awarded by the National Cancer Institute, Department of Health and
Funding Information:
Human Services, and in part by the Department of Energy (Contract DE-AC02-78EV04959 and Grant FG-0286ER60405) at New York University. The portion of the work carried out at the University of Chicago was supported by the American Cancer Society (Grant BC-132). We gratefully acknowledge the assistance of Dr. Y. Mnyukh in performing the linear dichroism measurements.
PY - 1988
Y1 - 1988
N2 - The modes of reaction of the tumorigenic bay region diol epoxide anti-BADE ((±)-trans-3,4-diol-anti-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene) and the less potent tumor initiating diastereomer syn-BADE ((±)-trans-3,4-diol-syn-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene) with native, double-stranded DNA were compared. The bay-region diol epoxide derived from 3-methylcholanthrene (3-MCDE, racemic trans-9,10-diol-anti-7,8-epoxy-7,8,9,10-tetrahydromethylcholanthrene) was included in this study in order to assess the effects of the methyl and methylene substituents on the reactivity with DNA. Utilizing linear dichroism and other spectroscopic methods, it is shown that all three diol epoxides form non-covalent complexes with DNA. The diastereomers anti-BADE and syn-BADE form intercalative physical complexes, but the association constant K of the syn-diastereomer is about 6-7 times smaller than for anti-BADE; this effect is ascribed to the bulky quasi-diaxial conformation of the diol epoxide ring in the syn diastereomer. The value of K (4000 M-1) is similar for anti-BADE and 3-MCDE, although the latter is not intercalated in the classical sense since the short axis of the molecule is tilted closer to the axis of the DNA double helix. The conformations of the covalent DNA adducts are interpreted in terms of a quasi-intercalative conformation (site I), and a conformation in which the long axes of the polycyclic molecules are tilted closer to the axis of the helix (site II). Both tumorigens, anti-BADE and 3-MCDE, undergo a marked reorientation from a non-covalent site I to a covalent site II conformation upon binding chemically with the DNA bases, although a small fraction of the covalent anti-BADE adducts remains quasi-intercalated; in contrast, the alkyl substituents in 3-MCDE not only prevent the formation of intercalative physical complexes, but also the formation of site I covalent adducts. In the case of the less tumorigenic syn-BADE, both the non-covalent complexes and the covalent adducts are of the site I-type. The bay-region diol epoxide of benz[a]anthracene and of 3-methylcholanthrene display a similar pattern of reactivities and covalent adduct conformations as the bay region diol epoxide derivatives of benz[a]pyrene, suggesting that adduct conformation might be an important factor in determining the levels of mutagenic and tumorigenic activities of this class of compounds.
AB - The modes of reaction of the tumorigenic bay region diol epoxide anti-BADE ((±)-trans-3,4-diol-anti-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene) and the less potent tumor initiating diastereomer syn-BADE ((±)-trans-3,4-diol-syn-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene) with native, double-stranded DNA were compared. The bay-region diol epoxide derived from 3-methylcholanthrene (3-MCDE, racemic trans-9,10-diol-anti-7,8-epoxy-7,8,9,10-tetrahydromethylcholanthrene) was included in this study in order to assess the effects of the methyl and methylene substituents on the reactivity with DNA. Utilizing linear dichroism and other spectroscopic methods, it is shown that all three diol epoxides form non-covalent complexes with DNA. The diastereomers anti-BADE and syn-BADE form intercalative physical complexes, but the association constant K of the syn-diastereomer is about 6-7 times smaller than for anti-BADE; this effect is ascribed to the bulky quasi-diaxial conformation of the diol epoxide ring in the syn diastereomer. The value of K (4000 M-1) is similar for anti-BADE and 3-MCDE, although the latter is not intercalated in the classical sense since the short axis of the molecule is tilted closer to the axis of the DNA double helix. The conformations of the covalent DNA adducts are interpreted in terms of a quasi-intercalative conformation (site I), and a conformation in which the long axes of the polycyclic molecules are tilted closer to the axis of the helix (site II). Both tumorigens, anti-BADE and 3-MCDE, undergo a marked reorientation from a non-covalent site I to a covalent site II conformation upon binding chemically with the DNA bases, although a small fraction of the covalent anti-BADE adducts remains quasi-intercalated; in contrast, the alkyl substituents in 3-MCDE not only prevent the formation of intercalative physical complexes, but also the formation of site I covalent adducts. In the case of the less tumorigenic syn-BADE, both the non-covalent complexes and the covalent adducts are of the site I-type. The bay-region diol epoxide of benz[a]anthracene and of 3-methylcholanthrene display a similar pattern of reactivities and covalent adduct conformations as the bay region diol epoxide derivatives of benz[a]pyrene, suggesting that adduct conformation might be an important factor in determining the levels of mutagenic and tumorigenic activities of this class of compounds.
KW - Benz[a]anthracene
KW - Benzo[a]pyrene
KW - Carcinogenesis
KW - DNA-carcinogen adducts
KW - Intercalation
KW - Linear dichroism
KW - Polycyclic aromatic hydrocarbon
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U2 - 10.1016/0009-2797(88)90046-4
DO - 10.1016/0009-2797(88)90046-4
M3 - Article
C2 - 3383284
AN - SCOPUS:0023949839
SN - 0009-2797
VL - 66
SP - 121
EP - 145
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1-2
ER -