P450 Enzymes

Abstract

Multiple hepatic P450 enzymes play an important role in the oxidative biotransformation of a vast number of structurally diverse drugs. As such, these enzymes are a major determinant of the pharmacokinetic behaviour of most therapeutic agents. There are several factors that influence P450 activity, either directly or at the level of enzyme regulation. Drug elimination is decreased and the incidence of drug interactions is increased when there is competition between 2 or more drugs for oxidation by the same P450 enzyme. The available knowledge concerning the relationship between the presence of certain functional groups within the drug structure and inhibition of P450 activity is increasing. In many instances, it is possible to associate inhibition with certain drug classes, e.g. antimycotic imidazoles and macrolide antibiotics. Disease states, especially those with hepatic involvement, and the genetic makeup of the individual are conditions in which some P450s may be downregulated (that is, the enzyme concentrations in liver are decreased), with associated slower rates of drug elimination. In these individuals, dosages of drugs that are substrates for downregulated P450s should be decreased. Exposure to environmental pollutants as well as a large number of lipophilic drugs can result in induction (upregulation) of P450 enzyme activity. This raises the issue of previous approaches to the study of P450 induction in vivo. The use of human hepatocyte preparations in culture is a promising new direction that could assist the determination of modifications to drug therapy necessitated by exposure to inducing agents. Until such information is obtained, however, the use of drugs known to increase the microsomal expression of particular P450s, and increase associated drug oxidation capacity in humans, should be used with caution.

Hepatoprotective activity ofGlycosmis pentaphyllaagainst paracetamol-induced hepatotoxicity in Swiss albino mice

“…Effect of treatment with paracetamol on the serum ALT activities The estimation was done by using a photoanalyser (FT-2; AMS); serum ALT determination was carried out with a suitable kit (Autospan Diagnostic Reagent) containing the necessary reagents at a predetermined wavelength 340 nm where the rate of oxidation of NADH is measured kinetically by monitoring the decrease in absorbance at 340 nm (Murray, 1994).…”

“…The rate of oxidation of NADH is measured kinetically by monitoring the decrease in absorbance at 340 nm and is directly proportional to GOT activity in the sample (Murray, 1994).…”

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

“…Many studies have shown the effects of liver disease on CYP enzyme expression, and also the involvement of CYPs in the pathogenesis of disease [ 174 , 175 ]. For instance, the expression of CYP1A2, CYP2E1 and CYP3A was found to be decreased in cirrhotic and HCC patients, together with an alteration in the clearance of drugs metabolized by CYP3A4 [ 176 , 177 ]. Similarly, the expression of various CYP enzymes was altered in patients with NAFLD and ALD [ 178 , 179 ].…”

Psychiatry, psychopharmacology and P-450s

“…In many cases this information is incomplete or unknown, especially for older compounds. There are substantial genetic differences in the level of expression of certain enzymes, and age, gender and environmental factors may also influence enzyme activity (see below; for more detailed information on this extensive topic see Watkins, 1990;Cholerton er af., 1992;Murray, 1992;Brosen, 1993). For a given substrate, CYP450 enzymes may also be divided into two functional classes, based on whether they produce active or inactive metabolites.…”

“…ketoconazole, a CYP3A4 inhibitor, may slow the metabolism of certain benzodiazepines; fluoxetine may inhibit metabolism of some beta-blockers). A few of these interactions will be mentioned below, however a detailed review of the relationship between CYP450 enzymes and non-psychotropic drugs is beyond the scope of this article (for review see Watkins, 1990;Murray, 1992;Wrighton and Stevens, 1992). It is also important to note the shortcomings of some of the information in this area.…”