Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin.
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.
Kumar
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S
Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York, College at Buffalo, Buffalo, NY 14222, USA.
Chang
R L
RL
Wood
A W
AW
Xie
J G
JG
Huang
M T
MT
Cui
X X
XX
Kole
P L
PL
Sikka
H C
HC
Balani
S K
SK
Conney
A H
AH
Jerina
D M
DM
D000166:Acridines / Q000633:toxicity*; D000287:Administration, Topical; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D051379:Mice; D012878:Skin Neoplasms / Q000139:chemically induced*; D013237:Stereoisomerism
D000166:Acridines; D001551:Benz(a)Anthracenes; D002273:Carcinogens; C022289:dibenzacridine; C079613:dibenz(a,h)anthracene-3,4-diol 1,2-oxide; C018914:dibenz(a,h)anthracene-1,2,3,4-tetrahydro-3,4-diol