Mechanism-based inactivation of benzo(a)pyrene hydroxylase by aryl acetylenes and aryl olefins
A series of aryl acetylenes and aryl olefins have been examined as substrates and inhibitors of cytochrome P-450 dependent monooxgenases in liver microsomes from 5,6-benzoflavone or phenobarbital pretreated rats. 1-Ethynylpyrene, 3-ethynylperylene, 2-ethynylfluorene, methyl 1-pyrenyl acetylene, cis- and trans-1-(2-bromovinyl)pyrene, and 1-allylpyrene serve as mechanism-based irreversible inactivators (suicide inhibitors) of benzo(a)pyrene hydroxylase, while 1-vinylpyrene and phenyl 1-pyrenyl acetylene do not cause a detectable suicide inhibition of benzo(a)pyrene hydroxylase. The mechanism-based loss of benzo(a)pyrene hydroxylase caused by the aryl acetylenes is not accompanied by a corresponding loss of the P-450 content of the microsomes (suicide destruction). The suicide inhibition by these aryl acetylenes therefore does not involve covalent binding to the heme moiety of the monooxygenase. Nevertheless, in the presence of NADPH, /sup 3/H-labeled 1-ethynylpyrene becomes covalently attached to the cytochrome P-450 protein; the measured stoichiometry of binding is one 1-ethynylpyrene per P-450 heme unit. The authors conclude that the inhibition of benzo(a)pyrene hydroxylase produced by 1-ethynylpyrene may be related to the mechanism of suicide inhibition of P-450 activity by chloramphenicol rather than the mechanism of suicide destruction of P-450 previously described for acetylene and propyne.
- Research Organization:
- Tulane Univ., New Orleans, LA
- OSTI ID:
- 5322268
- Report Number(s):
- CONF-8606151-
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 45:6; Conference: 76. annual meeting of the Federation of American Society for Experimental Biology, Washington, DC, USA, 8 Jun 1986
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ACETYLENE
BIOLOGICAL EFFECTS
ALKENES
HYDROXYLASES
ENZYME ACTIVITY
BIOCHEMICAL REACTION KINETICS
COVALENCE
INHIBITION
LIVER
MICROSOMES
NADP
PEPTIDES
RATS
SUBSTRATES
ALKYNES
ANIMALS
BODY
CELL CONSTITUENTS
COENZYMES
DIGESTIVE SYSTEM
ENZYMES
GLANDS
HYDROCARBONS
KINETICS
MAMMALS
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
OXIDOREDUCTASES
PROTEINS
REACTION KINETICS
RODENTS
VERTEBRATES
560301* - Chemicals Metabolism & Toxicology- Cells- (-1987)
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