>From: kohn at valiant.niehs.nih.gov ("Michael Kohn")
>Subject: Re: heterogeneous catalysis
>I encounter similar cases in my own work involving metabolism of xenobiotics
>by inducible enzymes bound to the hepatic endoplasmic reticulum. Olefinic
>chemicals are oxidized by several isoforms of cytochrome P450 to epoxides,
>which are converted to vicinal diols by the microsomal enzyme epoxide
>hydrolase. The net rate of accumulation of the epoxide intermediate cannot
>be reproduced by equations that treat these two enzymes as independent.
>Hydrolysis of an endogenously produced epoxide is more rapid than observed
>when"preformed" epoxide (not its precursor) is the exogenously supplied
>substrate. ....
Michael,
I'm sure that you are also aware of the issue of spacial enzyme localization
within the hepatic acinus, which appears to explain the "preferential"
conversion of endogenously formed phenol to hydroquinone, vs. the higher
sulfation of exogenously administered phenol. Even if EH is distributed
uniformly in the liver, the centilobular localization of P450 can give the
appearance of channeling but can be described adequately by treating the
liver as a series of well-mixed compartments in series, corresponding to
the different zones of the acinus. Has this been rulled out for olefins?
-Paul
