Regioselectivity in rat microsomal metabolism of benzo [a] pyrene: Evidence for involvement of two distinct binding sites

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Abstract

The metabolic profile of benzo[a] pyrene (BP) in cumene hydroperoxide-(CHP)-dependent reaction by male rat liver microsomes was dependent on CHP concentration. At 0.05 mM CHP, 3-hydroxy-BP was the major metabolite. Increase in CHP reduced 3-hydroxy-BP formation but increased BP quinone formation simultaneously. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene (PY) selectively inhibited quinone formation but enhanced 3-hydroxy-BP formation. Naphthalene (NP) had no effect on BP quinone formation but inhibited BP 3-hydroxylation. Phenanthrene (PA) and benz[a] anthracene (BA) inhibited effectively 3-hydroxy-BP formation but only slgithly quinone formation. BP binding to microsomal protein correlated to quinone formation and not BP 3-hydroxylation. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less efficient than the male. Quinones were consistently predominant metabolites and their formation was also inhibited by pyrene. Our data provide evidence that regioselectivity in BP metabolism involves at least two distinct binding sites. One site recognizes the benzo region of BP in BP 3-hydroxylation and the other recognizes the pyrene region in quinone formation. The different ratios of 3-hydroxy-BP to quinone formation by male and female rat liver microsomes suggest that the two binding sites are probably located at separate cytochrome P-450 isozymes.

Original languageEnglish (US)
Pages (from-to)113-126
Number of pages14
JournalChemico-Biological Interactions
Volume59
Issue numberC
DOIs
StatePublished - 1986

Fingerprint

Regioselectivity
Benzo(a)pyrene
Metabolism
Rats
Binding Sites
Hydroxylation
Liver Microsomes
Liver
Metabolome
Metabolites
Quinones
benzoquinone
Cytochrome P-450 Enzyme System
Isoenzymes
pyrene

Keywords

  • BA
  • BP
  • CHP
  • HPLC
  • NP
  • PA
  • PAH
  • PY
  • benz[a]anthracene
  • benzo[a]pyrene
  • cumene hydroperoxide
  • high pressure liquid chromatography
  • naphthalene
  • phenanthrene
  • polycyclic aromatic hydrocarbon
  • pyrene

ASJC Scopus subject areas

  • Toxicology

Cite this

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title = "Regioselectivity in rat microsomal metabolism of benzo [a] pyrene: Evidence for involvement of two distinct binding sites",
abstract = "The metabolic profile of benzo[a] pyrene (BP) in cumene hydroperoxide-(CHP)-dependent reaction by male rat liver microsomes was dependent on CHP concentration. At 0.05 mM CHP, 3-hydroxy-BP was the major metabolite. Increase in CHP reduced 3-hydroxy-BP formation but increased BP quinone formation simultaneously. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene (PY) selectively inhibited quinone formation but enhanced 3-hydroxy-BP formation. Naphthalene (NP) had no effect on BP quinone formation but inhibited BP 3-hydroxylation. Phenanthrene (PA) and benz[a] anthracene (BA) inhibited effectively 3-hydroxy-BP formation but only slgithly quinone formation. BP binding to microsomal protein correlated to quinone formation and not BP 3-hydroxylation. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less efficient than the male. Quinones were consistently predominant metabolites and their formation was also inhibited by pyrene. Our data provide evidence that regioselectivity in BP metabolism involves at least two distinct binding sites. One site recognizes the benzo region of BP in BP 3-hydroxylation and the other recognizes the pyrene region in quinone formation. The different ratios of 3-hydroxy-BP to quinone formation by male and female rat liver microsomes suggest that the two binding sites are probably located at separate cytochrome P-450 isozymes.",
keywords = "BA, BP, CHP, HPLC, NP, PA, PAH, PY, benz[a]anthracene, benzo[a]pyrene, cumene hydroperoxide, high pressure liquid chromatography, naphthalene, phenanthrene, polycyclic aromatic hydrocarbon, pyrene",
author = "Wong, {A. K L} and Ercole Cavalieri and Rogan, {Eleanor G}",
year = "1986",
doi = "10.1016/S0009-2797(86)80058-8",
language = "English (US)",
volume = "59",
pages = "113--126",
journal = "Chemico-Biological Interactions",
issn = "0009-2797",
publisher = "Elsevier Ireland Ltd",
number = "C",

}

TY - JOUR

T1 - Regioselectivity in rat microsomal metabolism of benzo [a] pyrene

T2 - Evidence for involvement of two distinct binding sites

AU - Wong, A. K L

AU - Cavalieri, Ercole

AU - Rogan, Eleanor G

PY - 1986

Y1 - 1986

N2 - The metabolic profile of benzo[a] pyrene (BP) in cumene hydroperoxide-(CHP)-dependent reaction by male rat liver microsomes was dependent on CHP concentration. At 0.05 mM CHP, 3-hydroxy-BP was the major metabolite. Increase in CHP reduced 3-hydroxy-BP formation but increased BP quinone formation simultaneously. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene (PY) selectively inhibited quinone formation but enhanced 3-hydroxy-BP formation. Naphthalene (NP) had no effect on BP quinone formation but inhibited BP 3-hydroxylation. Phenanthrene (PA) and benz[a] anthracene (BA) inhibited effectively 3-hydroxy-BP formation but only slgithly quinone formation. BP binding to microsomal protein correlated to quinone formation and not BP 3-hydroxylation. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less efficient than the male. Quinones were consistently predominant metabolites and their formation was also inhibited by pyrene. Our data provide evidence that regioselectivity in BP metabolism involves at least two distinct binding sites. One site recognizes the benzo region of BP in BP 3-hydroxylation and the other recognizes the pyrene region in quinone formation. The different ratios of 3-hydroxy-BP to quinone formation by male and female rat liver microsomes suggest that the two binding sites are probably located at separate cytochrome P-450 isozymes.

AB - The metabolic profile of benzo[a] pyrene (BP) in cumene hydroperoxide-(CHP)-dependent reaction by male rat liver microsomes was dependent on CHP concentration. At 0.05 mM CHP, 3-hydroxy-BP was the major metabolite. Increase in CHP reduced 3-hydroxy-BP formation but increased BP quinone formation simultaneously. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene (PY) selectively inhibited quinone formation but enhanced 3-hydroxy-BP formation. Naphthalene (NP) had no effect on BP quinone formation but inhibited BP 3-hydroxylation. Phenanthrene (PA) and benz[a] anthracene (BA) inhibited effectively 3-hydroxy-BP formation but only slgithly quinone formation. BP binding to microsomal protein correlated to quinone formation and not BP 3-hydroxylation. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less efficient than the male. Quinones were consistently predominant metabolites and their formation was also inhibited by pyrene. Our data provide evidence that regioselectivity in BP metabolism involves at least two distinct binding sites. One site recognizes the benzo region of BP in BP 3-hydroxylation and the other recognizes the pyrene region in quinone formation. The different ratios of 3-hydroxy-BP to quinone formation by male and female rat liver microsomes suggest that the two binding sites are probably located at separate cytochrome P-450 isozymes.

KW - BA

KW - BP

KW - CHP

KW - HPLC

KW - NP

KW - PA

KW - PAH

KW - PY

KW - benz[a]anthracene

KW - benzo[a]pyrene

KW - cumene hydroperoxide

KW - high pressure liquid chromatography

KW - naphthalene

KW - phenanthrene

KW - polycyclic aromatic hydrocarbon

KW - pyrene

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U2 - 10.1016/S0009-2797(86)80058-8

DO - 10.1016/S0009-2797(86)80058-8

M3 - Article

C2 - 3757144

AN - SCOPUS:0022886527

VL - 59

SP - 113

EP - 126

JO - Chemico-Biological Interactions

JF - Chemico-Biological Interactions

SN - 0009-2797

IS - C

ER -