Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.
Affiliation
School of Pharmacy, University of Southern California, Los Angeles 90033.Issue Date
1992-03-24
Metadata
Show full item recordAbstract
DT-diaphorase (DTD) mediated reduction of a series of 2,5-bis-substituted-3,6-diaziridinyl-1,4-benzoquinones was found to increase the level of DNA interstrand cross-linking (ISC) formed at neutral pH with an enhancement observed as the pH was decreased to 5.8. The analogues used were symmetrically alkyl-substituted carbamoyl ester analogues of AZQ (D1-D7), 3,6-diaziridinyl-1,4-benzoquinone (DZQ), the 2,5-dimethyl derivative (MeDZQ), and a 2,5-bis[(2-hydroxyethyl)amino] analogue (BZQ). At pH 5.8, the level of DNA ISC induced by enzymatic reduction was as follows: DZQ greater than MeDZQ much greater than D1 (methyl) greater than D3 (n-propyl) greater than D2 (AZQ; ethyl) greater than D5 (n-butyl) greater than D7 (sec-butyl) greater than D4 (isopropyl) D6 greater than (isobutyl). A similar trend was observed at pH 7.2. The level of DNA ISC induced by BZQ, which is not a substrate for DTD, was not increased by enzymatic reduction. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the DNA ISC induced by these quinones upon enzymatic reduction. MeDZQ and DZQ reacted with guanines, as measured by Maxam and Gilbert sequencing, with a sequence selectivity similar to that of the nitrogen mustard class of antitumor agents. Enzymatic reduction of DZQ and MeDZQ by DTD was found to alter their sequence-selective alkylation. Reduced DZQ showed enhanced guanine alkylation in 5'-GC-3' sequences and new sites of adenine alkylation in 5'-(A/T)AA-3' sequences. Reduced MeDZQ only showed new sites of adenine alkylation at 5'-(A/T)AA-3' sequences but no enhancement of guanine alkylation. The new sites of adenine alkylation were found to be inhibited in the presence of magnesium and rapidly converted into apurinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)Citation
Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase. 1992, 31 (11):3019-25 BiochemistryJournal
BiochemistryDOI
10.1021/bi00126a025PubMed ID
1372518Type
ArticleLanguage
enISSN
0006-2960ae974a485f413a2113503eed53cd6c53
10.1021/bi00126a025
Scopus Count
Collections
Related articles
- Relationship between DT-diaphorase-mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity.
- Authors: Gibson NW, Hartley JA, Butler J, Siegel D, Ross D
- Issue date: 1992 Sep
- DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.
- Authors: Hartley JA, Berardini M, Ponti M, Gibson NW, Thompson AS, Thurston DE, Hoey BM, Butler J
- Issue date: 1991 Dec 17
- Mapping of DNA alkylation sites induced by aziridinylbenzoquinones in human cells by ligation-mediated polymerase chain reaction.
- Authors: Lee CS, Pfeifer GP, Gibson NW
- Issue date: 1994 Apr 1
- Two structurally related diaziridinylbenzoquinones preferentially cross-link DNA at different sites upon reduction with DT-diaphorase.
- Authors: Berardini MD, Souhami RL, Lee CS, Gibson NW, Butler J, Hartley JA
- Issue date: 1993 Apr 6
- Induction of p21 mediated by reactive oxygen species formed during the metabolism of aziridinylbenzoquinones by HCT116 cells.
- Authors: Qiu X, Forman HJ, Schönthal AH, Cadenas E
- Issue date: 1996 Dec 13