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The role of prostaglandin H synthase (PHS) in the metabolism of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) has been examined in short-term explant cultures of hamster and human tracheobronchial tissues. Labeled BP-7,8-diol was incubated with the explants in the presence and absence of the PHS substrate arachidonic acid (20:4) and the PHS inhibitor indomethacin. The addition of 10 microM to 200 microM 20:4 to incubations of hamster trachea with 5 microM BP-7,8-diol caused significant increases in the formation of 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[ a]pyrene (anti-BPDE). These increases were not seen when 1 microM or 20 microM BP-7,8-diol was employed. The stimulation of anti-BPDE formation was observed after incubations of from 1 to 48 h. This stimulation was inhibited to the basal level by 20 microM indomethacin, supporting the role of PHS in the response. No effect of 20:4 was seen on the uptake of BP-7,8-diol by the tracheas or on the formation of water-soluble metabolites. Significant increases in covalent binding of BP-7,8-diol metabolites to DNA of the tracheal epithelium were also elicited by the addition of 20:4, however these increases were not well correlated quantitatively with the increases in anti-BPDE formation. H.p.l.c. profiles of deoxynucleoside adducts from basal and 20:4-stimulated incubations were qualitatively identical. Far greater variability of metabolism was seen in human bronchus explants, but 20:4-dependent increases in anti-BPDE formation could be demonstrated in those tissues as well. Inhibition of this stimulation by indomethacin was either absent or incomplete. This variation in the effect of indomethacin was explained by the examination of the products of 20:4 metabolism by the two tissues. Hamster trachea produced almost exclusively PHS metabolites whereas human bronchus yielded predominantly products of lipoxygenases, enzymes insensitive to indomethacin. In conclusion, this study indicates that co-oxygenation of chemical carcinogens can occur in hamster and human tracheobronchial tissues. The concentration-dependence observed with BP-7,8-diol, however, suggests that this pathway is of minor importance in the activation of BP in these tissues.
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
May 1984,
The Journal of biological chemistry,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
January 1982,
Drug metabolism reviews,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
July 1982,
Cancer research,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
November 1989,
Carcinogenesis,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
January 1981,
Chemico-biological interactions,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
August 1979,
Cancer research,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
November 1978,
Mutation research,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
March 1991,
Carcinogenesis,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
December 1986,
Carcinogenesis,
G A Reed, and
R C Grafstrom, and
R S Krauss, and
H Autrup, and
T E Eling
May 1980,
Biochemical and biophysical research communications,
