Substrate binding rates, microsomes

Gao and Hansch (1996) reported examples of P450 metabolism, specifically N-demethylation, where the overall rate of the reaction for the isolated enzyme, increased with increasing lipophilicity (as measured by log Kow). Further, it was shown to be independent of the electron donating or withdrawing effects of substituents, which appeared to have approximately equal and opposite effects on the two components, substrate binding, and reaction rate. For microsomes in vitro the lipophilicity was a particularly significant factor. 

The binding of sulfur and/or an activated intermediate of the phosphorus-containing portion of the parathion molecule to the endoplasmic reticulum leads to a decrease in the amount of cytochrome P-450 detectable as its carbon monoxide complex and to a decrease in the rate of metabolism of substrates such as benz-phetamine ( 19). Neither paraoxon nor any other isolatable metabolite of parathion decreases the amount of cytochrome P-450 or inhibits the ability of microsomes to metabolize substrates such a benzphetamine (19). 

Table VII shows the Increase In cytochrome P-450 content In mlcrosomes from southern armyworm larval midguts resulting from dietary exposure to several cyclic monoterpenes ( ). It also shows a closely corresponding Increase In the rate of NADPH oxidation when pyrethrum Is the substrate (R) being oxidised. The microsomal cytochrome P-450 system Is arranged as outlined In Figure 6, consisting of a terminal heme-lron protein that In the oxidised (Fe3+) state binds the substrate (R). The complex undergoes two reductions during which bound molecular oxygen Is converted to free radical species, one of which Is Inserted In the substrate molecule, and the other one forms water. The reductions...

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