On Jan 28, 8:57am, Paul M. Schlosser wrote:
> 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?
>-- End of excerpt from Paul M. Schlosser
Paul,
Yes, I'm aware of the elegant modeling Elaina Kenyon did with benzene
metabolism showing how the relative amounts of phenol and hydroquinone produced
could be understood by localization of the enzymes in different cells. I never
heard of such localization for epoxide hydrolase. The epoxide problem is the
reverse, anyway. A model which has free access to all enzymes overpredicts the
amount of epoxide secreted into the blood. If the olefin were oxidized in
centrilobular cells, the epoxide intermediate secreted into the sinusoids near
the central vein, and the epoxide absorbed by periportal cells at the beginning
of the sinusoid on the next pass of the blood through the liver, we'd expect
more epoxide in the blood than predicted by independent enzyme models not less
as is actually observed. We must find a mechanism that shields the intermediate
from exchange with the extracellular space. Both subcellular compartmentation
and privileged access solve this problem, but I'm not aware of any direct
evidence supporting either one.
Michael
--
Michael C. Kohn
Laboratory of Computational Biology and Risk Analysis
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop A3-06
Research Triangle Park, NC 27709-2233
Telephone:
919-541-4929 (voice)
919-541-1479 (fax)
e-mail:
kohn at valiant.niehs.nih.gov
WWW home page:
http://valiant.niehs.nih.gov
