Sv. Vulimiri et al., Analysis of highly polar DNA adducts formed in SENCAR mouse epidermis following topical application of dibenz[a,j]anthracene, CHEM RES T, 12(1), 1999, pp. 60-67
The formation of DNA adducts in mouse epidermis has been examined following
topical application of dibenz[a,j]anthracene (DB[a,j]A) and its metabolite
s, i.e., DB[a,j]A-3,4-diol, DB-[a,j]A-3,4-10,11-bis-diol, DB[a,j]A-3,4-8,9-
bis-diol, 10-OH-DB[a,j]A-3,4-diol, or 11-OH-DB[a,j]A-3,4-diol, using a P-32
-postlabeling assay. At initiating doses (400-1600 nmol), DB[a,j]A produced
at least 23 DNA adduct spots, including four less polar (derived from the
bay-region syn- and anti-diol-epoxides) and 19 highly polar DNA adducts. DB
[a,j]A-3,4-diol produced 13 DNA adduct spots, four less polar and nine high
ly polar DNA adducts, and DB[a,j]A-3,4-10,11-bis-diol produced nine highly
polar DNA adducts. Eight and seven of the highly polar DNA adducts generate
d by DB[a,j]A-3,4-diol and DB[a,j]A-3,4-10,11-bis-diol, respectively, migra
ted in the chromatography system like the highly polar DNA adducts produced
by the parent compound. Sufficient amounts of radioactivity were associate
d with highly polar adduct spots 11, 13, and 22 to confirm their chromatoga
phic identity in DNA samples from DB[a,j]A-, DB[a,j]A-3,4-diol-, and DB[a,j
]A-3,4-10,11-bis-diol-treated mice. 10-OH-DB[a,j]A-3,4-diol and 11-OH-DB-[a
,j]A-3,4-diol did not produce any highly polar DNA adducts that could be de
tected under our experimental conditions. At an initiating dose of 400 nmol
, DB[a,j]A, DB[a,j]A-3,4-diol, and DB[a,j]A-3,4-10,11-bis-diol produced 22.
4 +/- 13.0, 15.6 +/- 10.1, and 5.5 +/- 0.3 (mean +/- SD) adducts/10(9) nucl
eotides, of which 77, 65, and 100%, respectively, represented highly polar
DNA adducts. At the same dose of 400 nmol per mouse, DB[a,j]A and its 3,4-d
iol were able to initiate papillomas in SENCAR mouse skin (3.08 +/- 1.89 an
d 3.48 +/- 2.72 papillomas per mouse, respectively, after 16 weeks of promo
tion with 12-O-tetradecanoyl phorbol 13-acetate), while the 3,4-10,11-bis-d
iol of DB[a,j]A was inactive as a tumor initiator. A quantitative correlati
on (r = 0.935; p = 0.0196) between levels of less polar DNA adducts and tum
or-initiating activity of DB[a,j]A, DB[a,j]A-3,4-diol, and anti-DB[a,j]ADE
was observed. This study demonstrates that the highly polar DNA adducts for
med from DB[a,j]A in mouse epidermis arise primarily from the DB[a,j]A-3,4-
10,11-bis-diol. However, the contribution of this metabolite to the tumor-i
nitiating activity of DB[a,j]A appears to be small.