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
Rl. Chang et al., 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, CARCINOGENE, 21(11), 2000, pp. 1997-2003
The nitrogen heterocycle dibenz[c,h]acridine (DB[c,h]ACR) and the enantiome
rs of the diastereomeric pair of bay-region 3,4-diol 1,2-epoxides as well a
s other bay-region epoxides and dihydrodiol derivatives of this hydrocarbon
have been evaluated for tumorigenicity on mouse skin and in the newborn mo
use. On mouse skin, a single topical application of 50 or 200 nmol of compo
und was followed 10 days later by twice-weekly applications of the tumor pr
omoter 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. DB[c,h]ACR and th
e four optically pure, bay-region 3,4-diol-1,2-epoxide isomers all had sign
ificant tumor-initiating activity, The isomer with (1R,2S,3S,4R) absolute c
onfiguration [(+)-DE-2] was the most active diol epoxide isomer, The (-)-(3
R,3R)-dihydrodiol of DB[c,h]ACR, the expected metabolic precursor of the ba
y-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 d
ays 1, 8 and 15 of life, and tumorigenic activity was determined when the m
ice were 36-39 weeks old. DB[c,h]ACR produced a significant number of pulmo
nary tumors and also produced hepatic tumors in male mice. Of the four opti
cally active bayregion diol epoxides, only (+)-DE-2 and (+)-DE-1 with (1R,2
S,3S,4R) and (1S,2R,3S,4R) absolute configuration, respectively, produced a
significant tumor incidence. At an equivalent dose, the (+)-DE-2 isomer pr
oduced severalfold more pulmonary tumors and hepatic tumors than the (+)-DE
-1 isomer, The (-)-(3R,4R)-dihydrodiol, metabolic precursor of the bay-regi
on (+)-DE-2, was strongly active and induced an equal number of pulmonary a
nd hepatic tumors as did DB[c,lt]ACR. The (+)-(35,4S) 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)-enantiome
r was inactive. This contrasts with the data on mouse skin where both enant
iomers 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 mous
e 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 h
ydrocarbons.