TY - JOUR
T1 - Evidence for distinct binding sites in the cumene hydroperoxide-dependent metabolism of benzo[a]pyrene catalyzed by cytochrome P-450
AU - Cavalieri, Ercole
AU - Wong, Allan
AU - Rogan, Eleanor
N1 - Funding Information:
Acknowledgements-Thisr esearchw as supportedb y U.S. Public Health ServiceG rantsROl CA32376a ndCA36727 from the National Cancer Institute. The researcho f A. Wong was partially supportedb y a fellowship from the NebraskaD epartmento f Health. We gratefullya cknowl-edget he excellente ditorial assistanceo f Ms. M. Susman.
PY - 1987/2/15
Y1 - 1987/2/15
N2 - A few constitutive cytochrome P-450 isozymes in male rat liver microsomes catalyzed the metabolism of benzo[a]pyrene (BP) in cumene hydroperoxide (CHP)-dependent reactions, which produced predominantly 3-hydroxyBP and BP quinones. This process varied with the concentration of CHP. At 0.05 mM CHP, 3-hydroxyBP was the major metabolite. An increase in CHP concentration reduced 3-hydroxyBP formation but increased the level of BP quinones. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene selectively inhibited quinone formation and enhanced 3-hydroxyBP formation. Naphthalene, phenanthrene and benz[a] anthracene nonspecifically inhibited total metabolism. BP binding to microsomal protein correlated with quinone formation, suggesting a common precursor reactive intermediate. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less effective than that in the male. With females, quinones were the major metabolites at all CHP concentrations, and their formation was again modulated by pyrene. These data indicate that two distinct binding sites are responsible for the formation of 3-hydroxyBP and BP quinones.
AB - A few constitutive cytochrome P-450 isozymes in male rat liver microsomes catalyzed the metabolism of benzo[a]pyrene (BP) in cumene hydroperoxide (CHP)-dependent reactions, which produced predominantly 3-hydroxyBP and BP quinones. This process varied with the concentration of CHP. At 0.05 mM CHP, 3-hydroxyBP was the major metabolite. An increase in CHP concentration reduced 3-hydroxyBP formation but increased the level of BP quinones. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene selectively inhibited quinone formation and enhanced 3-hydroxyBP formation. Naphthalene, phenanthrene and benz[a] anthracene nonspecifically inhibited total metabolism. BP binding to microsomal protein correlated with quinone formation, suggesting a common precursor reactive intermediate. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less effective than that in the male. With females, quinones were the major metabolites at all CHP concentrations, and their formation was again modulated by pyrene. These data indicate that two distinct binding sites are responsible for the formation of 3-hydroxyBP and BP quinones.
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U2 - 10.1016/0006-2952(87)90347-9
DO - 10.1016/0006-2952(87)90347-9
M3 - Article
C2 - 3827935
AN - SCOPUS:0023139235
SN - 0006-2952
VL - 36
SP - 435
EP - 440
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -