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Inhibition by norharman of metabolism of benzo[a]pyrene by the microsomal mixed function oxidase of rat liver

Authors
Journal
Chemico-Biological Interactions
0009-2797
Publisher
Elsevier
Publication Date
Volume
32
Identifiers
DOI: 10.1016/0009-2797(80)90064-2
Disciplines
  • Biology

Abstract

Abstract The effect of norharman on the metabolism of ethyl acetate-soluble metabolic intermediates of benzo[ a]pyrene (BP), 9,10-dihydro-9,10-dihydroxybenzo[ a]pyrene (9,10-diol), 4,5- dihydro-4,5-dihydroxybenzo[ a]pyrene (4,5-diol), 7,8-dihydro-7,8-dihydroxybenzo[ a]pyrene (7,8-diol), benzo[ a]pyrene diones, 3-hydroxybenzo[ a]pyrene (3-OH-BP) and 9-hydroxybenzo[ a]pyrene (9-OH-BP), were studied. These metabolic intermediates were converted by microsomal enzymes to other more polar ethyl acetate-soluble metabolites and then finally to the water-soluble metabolites. Norharman inhibited markedly the disappearance of each metabolite added as a substrate. With high-pressure liquid chromatographic (HPLC) separation it was revealed that formation of more polar metabolite was more efficiently inhibited by norharman than the formation of less polar metabolite. Formation of water-soluble metabolite was most efficiently inhibited by norharman. The mechanisms of the inhibitory effect of norharman on BP metabolism were studied by difference spectroscopy. On the addition of norharman, microsomes showed a type II difference spectrum, while on the addition of BP, they showed a type I difference spectrum. 3-OH-BP and 4,5-diol also gave a type I spectrum. Thus both BP and its metabolites bind to the active center of P-450, whereas norharman binds to the sixth ligand position of the iron ion of P-450. Kinetic studies showed that the K m-value of microsomes for BP was 6.25 μM in the presence and absence of norharman. This indicated that norharman inhibits the metabolism of BP non-competitively.

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