How stereochemistry affects mutagenesis by N2-deoxyguanosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene

Configuration of the adduct bond is more important than those of the hydroxyl groups

Rajiv Shukla, Scott Jelinsky, Tongming Liu, Nicholas Geacintov, Edward L. Loechler

Research output: Contribution to journalArticle

Abstract

Previous work has shown that the major adduct from the (+)-anti diol epoxide of benzo[a]-pyrene (B[a]P), which forms at N2-deoxyguanosine [(+)- trans-anti-B[a]P-N2-dG], is capable of inducing either predominantly G → T mutations (~95%) in a 5'-TGC-3 sequence context or predominantly GA mutations (~80%) in a 5'-CGT-3' sequence context. This is likely to be attributable to the major adduct being in a different mutagenic conformation in each case. In the next phase of this work, the questions to be addressed are what conformation is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein reports on the mutations induced in a single sequence context by four stereoisomers of B[a]P-N2-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)- cis-. The (+)-trans- and (-)-cis-adducts show a remarkably similar mutational pattern with G → A mutations predominating (~80%). The (-)-trans- and (+)- cis-adducts also show a similar mutational pattern with a more even mixture of G → T, G → A, and G → C mutations. Each of these adducts has an adduct bond and three hydroxyl groups at four consecutive saturated carbons in the B[a]P moiety of the adduct; the stereochemistry at these four positions differs in each of the adducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S configuration for the adduct bond, although they are a mirror image vis-a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share the opposite adduct bond stereochemistry (R) but differ in the stereochemistry of their hydroxyl groups. Thus, there is a correlation suggesting that anti-B[a]P-N2-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.

Original languageEnglish (US)
Pages (from-to)13263-13269
Number of pages7
JournalBiochemistry
Volume36
Issue number43
DOIs
StatePublished - Oct 28 1997

Fingerprint

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Mutagenesis
Stereochemistry
Deoxyguanosine
Hydroxyl Radical
Benzo(a)pyrene
Mutation
Conformations
Stereoisomerism
Epoxy Compounds
Mirrors
Carbon

ASJC Scopus subject areas

  • Biochemistry

Cite this

How stereochemistry affects mutagenesis by N2-deoxyguanosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene : Configuration of the adduct bond is more important than those of the hydroxyl groups. / Shukla, Rajiv; Jelinsky, Scott; Liu, Tongming; Geacintov, Nicholas; Loechler, Edward L.

In: Biochemistry, Vol. 36, No. 43, 28.10.1997, p. 13263-13269.

Research output: Contribution to journalArticle

@article{f5204448e03547188a0dcdc8ffbd3e67,
title = "How stereochemistry affects mutagenesis by N2-deoxyguanosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene: Configuration of the adduct bond is more important than those of the hydroxyl groups",
abstract = "Previous work has shown that the major adduct from the (+)-anti diol epoxide of benzo[a]-pyrene (B[a]P), which forms at N2-deoxyguanosine [(+)- trans-anti-B[a]P-N2-dG], is capable of inducing either predominantly G → T mutations (~95{\%}) in a 5'-TGC-3 sequence context or predominantly GA mutations (~80{\%}) in a 5'-CGT-3' sequence context. This is likely to be attributable to the major adduct being in a different mutagenic conformation in each case. In the next phase of this work, the questions to be addressed are what conformation is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein reports on the mutations induced in a single sequence context by four stereoisomers of B[a]P-N2-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)- cis-. The (+)-trans- and (-)-cis-adducts show a remarkably similar mutational pattern with G → A mutations predominating (~80{\%}). The (-)-trans- and (+)- cis-adducts also show a similar mutational pattern with a more even mixture of G → T, G → A, and G → C mutations. Each of these adducts has an adduct bond and three hydroxyl groups at four consecutive saturated carbons in the B[a]P moiety of the adduct; the stereochemistry at these four positions differs in each of the adducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S configuration for the adduct bond, although they are a mirror image vis-a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share the opposite adduct bond stereochemistry (R) but differ in the stereochemistry of their hydroxyl groups. Thus, there is a correlation suggesting that anti-B[a]P-N2-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.",
author = "Rajiv Shukla and Scott Jelinsky and Tongming Liu and Nicholas Geacintov and Loechler, {Edward L.}",
year = "1997",
month = "10",
day = "28",
doi = "10.1021/bi971195z",
language = "English (US)",
volume = "36",
pages = "13263--13269",
journal = "Biochemistry",
issn = "0006-2960",
number = "43",

}

TY - JOUR

T1 - How stereochemistry affects mutagenesis by N2-deoxyguanosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene

T2 - Configuration of the adduct bond is more important than those of the hydroxyl groups

AU - Shukla, Rajiv

AU - Jelinsky, Scott

AU - Liu, Tongming

AU - Geacintov, Nicholas

AU - Loechler, Edward L.

PY - 1997/10/28

Y1 - 1997/10/28

N2 - Previous work has shown that the major adduct from the (+)-anti diol epoxide of benzo[a]-pyrene (B[a]P), which forms at N2-deoxyguanosine [(+)- trans-anti-B[a]P-N2-dG], is capable of inducing either predominantly G → T mutations (~95%) in a 5'-TGC-3 sequence context or predominantly GA mutations (~80%) in a 5'-CGT-3' sequence context. This is likely to be attributable to the major adduct being in a different mutagenic conformation in each case. In the next phase of this work, the questions to be addressed are what conformation is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein reports on the mutations induced in a single sequence context by four stereoisomers of B[a]P-N2-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)- cis-. The (+)-trans- and (-)-cis-adducts show a remarkably similar mutational pattern with G → A mutations predominating (~80%). The (-)-trans- and (+)- cis-adducts also show a similar mutational pattern with a more even mixture of G → T, G → A, and G → C mutations. Each of these adducts has an adduct bond and three hydroxyl groups at four consecutive saturated carbons in the B[a]P moiety of the adduct; the stereochemistry at these four positions differs in each of the adducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S configuration for the adduct bond, although they are a mirror image vis-a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share the opposite adduct bond stereochemistry (R) but differ in the stereochemistry of their hydroxyl groups. Thus, there is a correlation suggesting that anti-B[a]P-N2-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.

AB - Previous work has shown that the major adduct from the (+)-anti diol epoxide of benzo[a]-pyrene (B[a]P), which forms at N2-deoxyguanosine [(+)- trans-anti-B[a]P-N2-dG], is capable of inducing either predominantly G → T mutations (~95%) in a 5'-TGC-3 sequence context or predominantly GA mutations (~80%) in a 5'-CGT-3' sequence context. This is likely to be attributable to the major adduct being in a different mutagenic conformation in each case. In the next phase of this work, the questions to be addressed are what conformation is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein reports on the mutations induced in a single sequence context by four stereoisomers of B[a]P-N2-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)- cis-. The (+)-trans- and (-)-cis-adducts show a remarkably similar mutational pattern with G → A mutations predominating (~80%). The (-)-trans- and (+)- cis-adducts also show a similar mutational pattern with a more even mixture of G → T, G → A, and G → C mutations. Each of these adducts has an adduct bond and three hydroxyl groups at four consecutive saturated carbons in the B[a]P moiety of the adduct; the stereochemistry at these four positions differs in each of the adducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S configuration for the adduct bond, although they are a mirror image vis-a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share the opposite adduct bond stereochemistry (R) but differ in the stereochemistry of their hydroxyl groups. Thus, there is a correlation suggesting that anti-B[a]P-N2-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.

UR - http://www.scopus.com/inward/record.url?scp=0030783590&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030783590&partnerID=8YFLogxK

U2 - 10.1021/bi971195z

DO - 10.1021/bi971195z

M3 - Article

VL - 36

SP - 13263

EP - 13269

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 43

ER -