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The following message was posted to: PharmPK
I'm working on in-vitro-studies to see influences of designer drugs (like
MDMA, "XTC", and Amphetamine) on the metabolism of THC, the active component
of cannabis. Working with human hepatic micromosmes, THC is metabolized
mainly to Hydroxy-THC (by CYP2C9), but also to a lot of other metabolites.
If I start an THC-metabolism-assay with MDMA, I found out that at high MDMA
concentrations (300=B5M, pre-incubated 2 =BD min) there is a soft increase o=
Hydroxy-THC be formed (we did GC-MS analysis). At low MDMA concentration
levels, the amound of formed Hydroxy-THC seems to be constant. Well, now I
have to figure out if the increase is analytically significant, but generall=
Can we talk of "induction" at in-vitro-systems?
While discussing, the theory arose that MDMA (or one of its metabolites) may
inhibit CYP enzymes which are representative for the transformation of other
THC metabolites. Therefore, the balance is slightly impaired; the formation
of other THC metabolites than Hydroxy-THC is inhibited/stopped, and more
Hydroxy-THC can be formed.
Do anybody know papers decribing this kind of "indirect induction of product
X by inhibition of product Y"?
Thank you very very much
University of Saarland
Institute of Legal Medicine, Toxicology
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Induction in vitro is possible, but only in systems with intact protein
biosynthesis (hepatocytes, precision-cut liver slices, etc.). In isolated
microsomes you may experience a co-oxygenation. I observed a similar
phenomenon with benzo(a)pyrene and its 7,8-dihydrodiol which was
co-oxygenated by many xenobiotics metabolized through a pathway
involving free radicals.
For reference, see:
Byczkowski,J.Z. & Kulkarni,A.P.: Lipid Peroxidation-Coupled
Co-Oxygenation of Benzo(a)pyrene and Benzo(a)pyrene-7,8-dihydrodiol
in Human Term Placental Microsomes. Placenta 11: 17-26, 1990.
Byczkowski,J.Z. & Kulkarni,A.P.: Lipid Peroxidation and
Benzo(a)pyrene Derivative Co-Oxygenation by Environmental Pollutants.
Bull. Environ. Contam. Toxicol. 45: 633-640, 1990.
Byczkowski,J.Z., & Kulkarni,A.P.: Vanadium redox cycling, lipid
peroxidation and co-oxygenation of benzo(a)pyrene-7,8-dihydrodiol.
Biochem. Biophys. Acta 1125: 134-141, 1992.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
212 N. Central Ave.
Fairborn, OH 45324
JZB Consulting web site: http://members.delphi.com/januszb/
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