Journal Article

Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin

Subodh Kumar, Richard L. Chang, Alexander W. Wood, Jian Guo Xie, Mou Tuan Huang, Xiao Xing Cui, Panna L. Kole, Harish C. Sikka, Suresh K. Balani, Allan H. Conney and Donald M. Jerina

in Carcinogenesis

Volume 22, issue 6, pages 951-955
Published in print June 2001 | ISSN: 0143-3334
Published online June 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.6.951
Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin

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CD-1 female mice were initiated with a single topical application of 500 nmol dibenz[a,h]acridine (DB[a,h]Acr), its racemic trans-1,2-, 3,4-, 8,9- and 10,11-dihydrodiols, racemic DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 or racemic DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, where the benzylic hydroxyl group is either cis (isomer 1) or trans (isomer 2) to the epoxide oxygen. The mice were subsequently treated twice weekly with 12-O-tetradecanoylphorbol 13-acetate for 25 weeks. High tumorigenicity was observed only for DB[a,h]Acr, its 10,11-dihydrodiol and DB[a,h]Acr 10,11-diol 8,9-epoxide-2 (3.3, 1.2 and 1.6 tumors/mouse, respectively). The tumor-initiating activity of a 50 nmol dose of DB[a,h]Acr and the optically active (+)- and (–)-enantiomers of DB[a,h]Acr 10,11-dihydrodiol and of the optically active DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2 were also studied. Only DB[a,h]Acr, (–)-DB[a,h]Acr (10R,11R)-dihydrodiol and the bay region (+)-(8R,9S,10S,11R)-diol epoxide-2 were highly active (1.6, 1.7 and 2.4 tumors/mouse, respectively). These results are consistent with previous studies which showed that the corresponding bay region RSSR diol epoxides of benzo[a]pyrene, benz[a]anthracene, chrysene and benzo[c]phenanthrene as well as the aza-polycyclic dibenz[c,h]acridine are the most tumorigenic isomers.

Keywords: PAH, polycyclic aromatic hydrocarbon; DB[a,h]Acr, dibenz[a,h]acridine; dihydrodiols, the trans-dihydroxydihydro derivatives in which the hydroxyl groups are at either the 1,2-, 3,4-, 8,9- or 10,11-positions; (±)-DB[a,h]Acr 3,4-diol 1,2-epoxide-1, (±)-3α, 4β-dihydroxy-1β, 2β-epoxy-1,2,3,4-tetrahydrodibenz[a,h]acridine in which the benzylic hydroxyl group and the epoxide oxygen are cis; (±)-DB[a,h]Acr 3,4-diol 1,2-epoxide-2, (±)-3α, 4β-dihydroxy-1α,2α-epoxy-1,2,3,4-tetrahydrodibenz[a,h] acridine in which the benzylic hydroxyl group and the epoxide oxygen are trans; other diol epoxides are similarly designated; (–)-(8S,9R, 10S,11R)-diol epoxide-1, (–)-(10S, 11R)-dihydroxy-(8S,9R)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (+)-(8R, 9S,10R, 11S)-diol epoxide-1, (+)-10R, 11S)-dihydroxy-(8R,9S)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (–)-(8S,9R,10R,11S)-diol epoxide-2, (–)-(10R,11 S)-dihydroxy-(8S,9R)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (+)-(8R, 9S,10S,11R)-diol epoxide-2, (+)-(10S, 11R)-dihydroxy-(8R, 9S)-epoxy-8,9,10,11-tetrahydro-dibenz[a,h]acridine; PAH, polycyclic aromatic hydrocarbon. The designations α and β denote opposite faces of the hydrocarbon in the racemic compounds.

Journal Article.  3742 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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