Journal Article

Tumorigenicity of four optically active bay-region 3,4-diol 1,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[<i>c,h</i>]acridine on mouse skin and in newborn mice

Richard L. Chang, Alexander W. Wood, Subodh Kumar, Roland E. Lehr, Naohiro Shirai, Donald M. Jerina and Allan H. Conney

in Carcinogenesis

Volume 21, issue 11, pages 1997-2003
Published in print November 2000 | ISSN: 0143-3334
Published online November 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.11.1997
Tumorigenicity of four optically active bay-region 3,4-diol 1,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h]acridine on mouse skin and in newborn mice

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The nitrogen heterocycle dibenz[c,h]acridine (DB[c,h]ACR) and the enantiomers of the diastereomeric pair of bay-region 3,4-diol 1,2-epoxides as well as other bay-region epoxides and dihydrodiol derivatives of this hydrocarbon have been evaluated for tumorigenicity on mouse skin and in the newborn mouse. On mouse skin, a single topical application of 50 or 200 nmol of compound was followed 10 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. DB[c,h]ACR and the four optically pure, bay-region 3,4-diol-1,2-epoxide isomers all had significant tumor- initiating activity. The isomer with (1R,2S,3S,4R) absolute configuration [(+)-DE-2] was the most active diol epoxide isomer. The (–)-(3R,4R)-dihydrodiol of DB[c,h]ACR, the expected metabolic precursor of the bay-region (+)-DE-2, was 4- to 6-fold more tumorigenic than its corresponding (+)-enantiomer. In tumorigenicity studies in newborn mice, a total dose of 70–175 nmol of DB[c,h]ACR or one of its derivatives was injected i.p. on days 1, 8 and 15 of life, and tumorigenic activity was determined when the mice were 36–39 weeks old. DB[c,h]ACR produced a significant number of pulmonary tumors and also produced hepatic tumors in male mice. Of the four optically active bay-region diol epoxides, only (+)-DE-2 and (+)-DE-1 with (1R,2S,3S,4R) and (1S,2R,3S,4R) absolute configuration, respectively, produced a significant tumor incidence. At an equivalent dose, the (+)-DE-2 isomer produced several-fold more pulmonary tumors and hepatic tumors than the (+)-DE-1 isomer. The (–)-(3R,4R)-dihydrodiol, metabolic precursor of the bay-region (+)-DE-2, was strongly active and induced an equal number of pulmonary and hepatic tumors as did DB[c,h]ACR. The (+)-(3S,4S) dihydrodiol was less active. The bay-region (+)-(1R,2S)-epoxide of 1,2,3,4-tetrahydro DB[c,h]ACR was strongly tumorigenic in newborn mice whereas its (–)-(1S,2R)-enantiomer was inactive. This contrasts with the data on mouse skin where both enantiomers had substantial tumorigenic activity. In summary, the bay-region (+)-(1R,2S,3S,4R)-3,4-diol 1,2-epoxide of DB[c,h]ACR was the most tumorigenic of the four optically active bay-region diol epoxides of DB[c,h]ACR on mouse skin and in the newborn mouse. These results with a nitrogen heterocycle are similar to earlier data indicating high tumorigenic activity for the R,S,S,R bay-region diol epoxides of several carbocyclic polycyclic aromatic hydrocarbons.

Keywords: DB[c,h]ACR, dibenz[c,h]acridine; (+)-DE-1, (+)-(1S,2R 3S,4R)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrodibenz[c,h]acridine and (–)-DE-1 its (–)-(1R,2S,3R,4S)-enantiomer;; (+)-DE-2, (+)-(1R,2S,3S,4R)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrodibenz[c,h]acridine and (–)-DE-2, its (–)-(1S,2R,3R,4S)-enantiomer (the designations 1 and 2 for the diol epoxides indicate that the benzylic 4-hydroxyl group and the epoxide oxygen are cis or trans, respectively); DMSO, dimethyl sulfoxide; 3,4-H2-DB[c,h]ACR, 3,4-dihydrodibenz[c,h]acridine; dihydrodiols; the trans dihydroxydihydro derivatives of dibenz[c,h]acridine in which the hydroxyl groups are at the 1,2-, 3,4- or 5,6-positions; H4-diols, the trans-dihydroxytetrahydro derivatives of dibenz[c,h]acridine in which the hydroxyl groups are at the 1,2- or 3,4-positions; (±)-H4-1,2-epoxide, (±)-1,2-epoxy-1,2,3,4-tetrahydrodibenz [c,h]acridine; (+)-H4-1,2-epoxide, the (+)-(1R,2S)-enantiomer and (–)-H4-1,2-epoxide, the (–)-(1S,2R)-enantiomer; (±)-H4-3,4-epoxide, (±)-3,4-epoxy-1,2,3,4-tetrahydrodibenz[c,h]acridine; PAH, polycyclic aromatic hydrocarbon.

Journal Article.  5093 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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