title: 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.
abstract: 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.
authors.affiliation: Laboratory for Cancer Research, Rutgers, The State University of New Jersey, College of Pharmacy, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Chang
authors.forename: A W
authors.initials: AW
authors.lastname: Wood
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: R E
authors.initials: RE
authors.lastname: Lehr
authors.forename: N
authors.initials: N
authors.lastname: Shirai
authors.forename: D M
authors.initials: DM
authors.lastname: Jerina
authors.forename: A H
authors.initials: AH
authors.lastname: Conney
mesh_terms: D000166:Acridines / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D018383:Bay-Region, Polycyclic Aromatic Hydrocarbon; D002273:Carcinogens / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D051379:Mice; D011247:Pregnancy; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D000166:Acridines; D002273:Carcinogens; D004852:Epoxy Compounds; C022289:dibenzacridine; D013755:Tetradecanoylphorbol Acetate