Direct Cytochrome P450 Inhibition

2 CYP Inhibition Studies Using Recombinant P450 Isoenzymes. 552 

3 CYP Inhibition Studies Using Human Liver Microsomes 554 

4 CYP Inhibition Studies Using Isolated/Cultured Hepatocytes or Liver Slices 557 

The following discussions and assay descriptions are related to cytochrome P450 inhibition. Most drug interaction studies are related to P450 isoenzymes. Nevertheless, other enzyme systems may contribute to significant drug interactions such as transporter (e.g. Floren 1997 Abel 2001) phase II enzymes (e.g. Diet-mann 1976 Zucker 2001 Rayer 2001 Williams 2004), or cytosolic enzymes (Obach 2004). Additional assays related to pgp, phase II or cytosolic enzyme interactions are published in literature (e.g. Polli 2001 Schwab 2002 Schinkel 2003 www.bdbiosciences.com, Obach 2004). 

Inhibitory drug interactions generally fall into two categories. The first involves direct inhibition of the metabolism of one drug by the other. Direct inhibition may exhibit Michaelis-Menten kinetic characteristics 

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To better understand the health effects of plant phenolic compounds and to better utilize them, it is necessary to know the molecular mechanisms by which plant phenolic compounds induce cytoprotective enzymes. In vitro studies indicated that plant phenolic compounds such as curcumin often inhibited the enzymatic activities of GST, UGT, SULT as well as cytochrome P450s [Oetari et al., 1996], suggesting that the induction of cytoprotective enzyme activities could not be explained by direct interaction with plant phenolic compounds. On the other hand, much evidence indicates that the increased activity of cytoprotective enzymes are mainly attributable to enhanced transcriptional activation and enzyme synthesis [Holtzclaw et al., 2004]. 

The symptoms may have been due to a direct effect of clarithromycin or else inhibition of hepatic cytochrome P450 metabolism, leading to fluoxetine toxicity. Clarithromycin occasionally causes hallucinations. 

Figure 16.2. Mechanisms of cellular toxicity. Tissues are comprised of cells, and each cell is defined by its cell membrane. The cell membrane is composed of a lipid bilayer, which contains proteins that function as ion channels and receptors. Compounds that disrupt the membrane environment can directly or indirectly alter the normal function of these proteins. In each cell, there are numerous subcellular organelles, all of which are potential targets for toxicity. Cytochrome P450 enzymes in the endoplasmic reticulum may metabolize drugs that enter the cell. Metabolism has one of two effects on the drug s potential toxicity (l)it may reduce toxicity by eliminatingparent compound, or (2) it may increase toxicity by generating a reactive (electrophilic) metabolite. Drugs may inhibit critical functions in mitochondria or damage DNA in the nucleus, which can lead to cell death by apoptosis or necrosis.

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