Metabolic activation studies o
f dibenzo[
a,
l]py
rene (DB[
a,
l]P) (dibenzo[
def,
p]ch
rysene), anext
remely potent envi
ronmental ca
rcinogen, have been
focused on metabolism at the
fjo
rd
region, a
region associated with high mutagenic and ca
rcinogenic activities o
f the co
rresponding
fjo
rd-
region DB[
a,
l]P-11,12-diol-13,14-epoxides. DB[
a,
l]P is metabolized by
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flavone(BNF)- and 3-methylcholanth
rene-induced
rat live
r mic
rosomes and a
recombinant humanP450 1A1 system to two majo
r dihyd
rodiols, the K-
region dihyd
rodiol, DB[
a,
l]P-8,9-dihyd
rodiol(DB[
a,
l]P-8,9-diol), and the
fjo
rd-
region dihyd
rodiol, DB[
a,
l]P-11,12-dihyd
rodiol. We haveinvestigated the
fu
rthe
r metabolic activation o
f DB[
a,
l]P-8,9-diol by BNF-induced
rat live
rmic
rosomes and a
recombinant human P450 1A1 system with epoxide hyd
rolase to DB[
a,
l]P-bis-diols and to DNA adducts. (±)-
trans-DB[
a,
l]P-8,9-diol was synthesized and
resolved intoits enantiome
rs. Racemic
trans-DB[
a,
l]P-8,9-diol was metabolized by BNF-induced
rat live
rmic
rosomes to six metabolites: two diaste
reome
rs o
f trans,
trans-DB[
a,
l]P-8,9:11,12-bis-diol,two diaste
reome
rs o
f trans,
cis-DB[
a,
l]P-8,9:11,12-bis-diol, and two diaste
reome
rs o
f trans-DB[
a,
l]P-8,9:13,14-bis-diol as cha
racte
rized by NMR, MS, and UV spect
roscopy. Metabolic studiesusing both enantiome
ric (-)- and (+)-
trans-DB[
a,
l]P-8,9-diol
fu
rthe
r demonst
rated that eachdiaste
reome
r o
f trans,
trans-DB[
a,
l]P-8,9:11,12-bis-diol and
trans-DB[
a,
l]P-8,9:13,14-bis-diol wascomp
rised o
f two enantiome
rs. Simila
rly, incubations o
f enantiome
ric o
r racemic
trans-DB[
a,
l]P-8,9-diol with a
recombinant human P450 1A1 system and epoxide hyd
rolase also gavethe same two enantiome
ric mixtu
res o
f diaste
reome
rs o
f trans,
trans-DB[
a,
l]P-8,9:11,12-bis-diol and the same two enantiome
ric mixtu
res o
f diaste
reome
rs o
f trans-DB[
a,
l]P-8,9:13,14-bis-diol. This suggested that the mic
rosomal oxidations o
f (-)- and (+)-
trans-DB[
a,
l]P-8,9-diolwe
re ste
reospeci
fic. The ste
reospeci
fic
fo
rmation o
f enantiome
rs o
f trans-DB[
a,
l]P-8,9-diol
fromDB[
a,
l]P was examined using both BNF-induced
rat live
r mic
rosomes and a
recombinant humanP450 1A1 system with epoxide hyd
rolase. Ste
reospeci
ficity was obse
rved as both metabolicsystems
favo
red the
fo
rmation o
f (-)-
trans-DB[
a,
l]P-8,9-diol by 8-9-
fold. DNA adduct studieswe
re unde
rtaken using TLC/HPLC
32P-postlabeling techniques. In the p
resence o
f a
recombinant human P450 1A1 system with epoxide hyd
rolase, DB[
a,
l]P gave two g
roups o
f cal
fthymus DNA adducts. The g
roup o
f late
r-eluting adducts we
re identi
fied as a
rising
from
syn-and
anti-DB[
a,
l]P-11,12-diol-13,14-epoxides, while the mo
re pola
r ea
rly-eluting adducts we
rede
rived, in pa
rt,
from the
fu
rthe
r activation o
f trans-DB[
a,
l]P-8,9-diol. Ou
r data indicate that,in P450 1A1-mediated mic
rosomal incubations, DB[
a,
l]P is metabolized to
trans-DB[
a,
l]P-8,9-diol which is
fu
rthe
r metabolized to DB[
a,
l]P-bis-diols.
trans-DB[
a,
l]P-8,9-diol is metabolicallyactivated to inte
rmediates that can bind to DNA and give DNA adducts simila
r to thoseobse
rved with DB[
a,
l]P. These
results indicate that DB[
a,
l]P can be metabolically activatedby both
fjo
rd-
region and K-
region pathways.