Nm. Johnsen et al., METABOLISM AND ACTIVATION OF CYCLOPENTA POLYCYCLIC AROMATIC-HYDROCARBONS IN LIVER-TISSUE FROM RATS AND HUMANS, Chemico-biological interactions, 113(3), 1998, pp. 217-237
The metabolism of radiolabeled benz(j)aceanthrylene (B(j)A) was studie
d by high performance liquid chromatography (HPLC) using suspensions o
f hepatocytes and liver microsomes from control- or Aroclor 1254 (PCB)
-treated rats, or with human liver microsomes (five different donors)
as activation systems, The major metabolites formed in hepatocytes wer
e sulfate conjugates, indicating that sulfation is an important detoxi
cation pathway for B(j)A. In incubations with B(j)A and rat or human l
iver microsomes, the major metabolite formed was B(j)A-1,2-diol. Studi
es with rat liver microsomes using antibodies (Ab) towards either P450
1A1, 1A2 or 3A2, resulted in approximately 30% reduction in covalent b
inding with all Ab-using microsomes from control animals, whereas with
microsomes from PCB-treated animals an 85% reduction was observed usi
ng Ab towards P4501A2, and only minor reductions were observed with 1A
1 or 3A2. When compared to B(j)A and benzo(a)pyrene (B(a)P), benz(1)ac
eanthrylene (B(1)A) caused higher numbers of revertants in the Salmone
lla assay when plated with rat liver microsomes from control animals o
r human liver microsomes. The total DNA adduct levels in hepatocytes f
rom control animals after 2 h exposure to 30 mu g/ml (120 mu M) B(j)A
or B(1)A, as measured by the P-32-postlabelling technique, were 3.8 +/
- 1.5 and 10.1 +/- 5.8 fmol/mu g DNA, respectively. PCB-treatment decr
eased the total level of B(j)A adducts slightly (1.8 +/- 0.5 fmol/mu g
DNA), whereas in contrast the level of B(1)A adducts was increased (2
4.5 +/- 20.1 fmol/mu g DNA). The major DNA adduct formed in control he
patocytes exposed to B(j)A co-chromatographed with B(j)A-1,2-oxide, wh
ich also appeared to be the major adduct formed when rat or human live
r microsomes were co-incubated with calf thymus DNA. The total DNA add
uct levels in the modified calf thymus DNA after 30 min exposure to 30
mu g/ml B(j)A, B(1)A or B(a)P using rat liver microsomes from control
animals, were 3.6, 66.3 and 1.4 fmol/mu g DNA, respectively. These le
vels increased to 22.7, 93.3 and 7.4 fmol/mu g DNA, respectively, usin
g microsomes from PCB-treated animals. With human liver microsomes, th
e total DNA adduct levels after exposure to B(j)A, B(I)A or B(a)P, ran
ged between 0.4-1.0, 0.3-4.3, and 0.1-0.3 fmol/mu g DNA, respectively.
Overall, the present data supports the notion that oxidation at the c
yclopenta-ring is an important activation pathway for B(j)A, and indic
ate that the activation mechanism for B(j)A is similar in rat and huma
n liver tissue. (C) 1998 Elsevier Science Ireland Ltd. All rights rese
rved.