Authors: Duisken, Mike; Benz, Dorina; Peiffer, Thomas H.; Blomeke, Brunhilde; Hollender, Juliane

Source: Current Drug Metabolism, Volume 6, Number 6, December 2005 , pp. 593-601(9)

Publisher: Bentham Science Publishers

Abstract:

The metabolism of the bicyclic monoterpene Δ³-carene was investigated in vitro using human liver microsomes as well as human smoker/non-smoker lung microsomes and 12 different recombinant cytochrome P450 enzymes coexpressed with human CYP-reductase in Escherichia coli cells. We detected two metabolites using GC-MS analysis. The mass fragmentation indicated for one metabolite hydroxylation in the allyl position and for the other metabolite epoxidation at the double bond. For clear identification the suggested metabolites were synthesized in a four-step reaction. Comparison of GC retention times and mass spectra lead to the identification of the metabolites as Δ³-carene-10-ol ((1S, 6R)- 7,7-Dimethylbicyclo[4.1.0]hept-3-en-3-yl-methanol) and Δ³-carene-epoxide ((1S, 3S, 5R, 7R)-3,8,8-Trimethyl-4-oxatricyclo[ 5.1.0.03,5]octane). Δ³-carene-10-ol was formed by human liver microsomes and recombinant human CYP2B6, CYP2C19 and CYP2D6. Δ³-Carene-epoxide was obviously catalyzed only by CYP1A2. In both cases there was a clear correlation between the metabolite formation, incubation time and enzyme concentration, respectively. Further kinetic analysis revealed that CYP2B6 exhibited the highest activity for Δ³-carene 10-hydroxylation. Michaelis-Menten Km and Vmax for oxidation of Δ³-carene were 0.6 mM and 28.4 nmol/min/nmol P450 using human CYP2B6. For the formation of Δ³-carene-epoxide 98.2 mM and 3.9 nmol/min/nmol P450 were determined as Km and Vmax by using human CYP1A2. To our knowledge, this is the first time that Δ³-carene-10-ol and Δ³-carene-epoxide are described as human metabolites of Δ³- carene.

Keywords: Metabolism; Δ³-Carene; Cytochrome P450; Δ³-Carene-10-ol; Δ³-Carene-epoxide

Document Type: Review article

Affiliations: 1: Environmental Chemistry, Eawag, Uberlandstrasse 133, CH-8600 Dubendorf, Switzerland.

Publication date: 2005-12-01

More about this publication?

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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