Studies on the autoinactivation behavior of pure, reconstituted phenobarbital-induced cytochrome P-450 isozyme from rat liver.
NADPH-dependent turnover of O2, uncoupled from cosubstrate hydroxylation, in a reconstituted phospholipid system containing the cytochrome P-450 isozyme purified from the liver microsomes of phenobarbital-induced rats results in autocatalytic inactivation of this P-450 isozyme. At NADPH concentrations of 1.0 mM, half-times for inactivation are 7 to 9 min and reflect processing of 800 molecules of NADPH/enzyme molecule before an inactivation event occurs. Addition of saturating amounts of N,N-dimethylaniline leads to a 3-fold increase of Vmax of NADPH utilization with 40% of these extra molecules providing electrons for the hydroxylation/N-demethylation sequence. About 2300 turnovers occur over the time period of inactivation, with about 425 product formaldehyde molecules being generated in this interval. This inactivation does not occur in intact microsomes from the livers of phenobarbital-treated rats; however, solubilization of the microsomes or addition of exogenous pure reductase renders the P-450 susceptible to the same autoinactivation.[1]References
- Studies on the autoinactivation behavior of pure, reconstituted phenobarbital-induced cytochrome P-450 isozyme from rat liver. Loosemore, M., Light, D.R., Walsh, C. J. Biol. Chem. (1980) [Pubmed]
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