Role and modulation of major cytochrome P-450 families in health and liver diseases
(1996)
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- Authors
- Supervisors
- Geubel, André
- Abstract
- Cytochrome P-450 is a superfamily of enzymes which is mainly located in the reticulum endoplasmic of hepatocytes and represents the main pathways for durg oxidation. <BR> This superfamily is classified into families, subfamilies and/or single enzymes. Using this nomenclature, the majority of P-450’s involved in drug metabolism appear to belong to three distinct families, termed CYP1, CYP2 and CYP3. <BR> The activity of these enzymes is modulated by genetic, and/or non-genetic factors (age, sex, diet, tobacco, alcohol, drug, consumption …) as well as pathological conditions. <BR> Invasive and non-invasive methods have been developed to quantify these enzyme activities. <BR> Among invasive techniques, determination of CYP activities in liver microsomes is the most largely used however requiring large amounts of tissue. Tissue immunoquantification and the more recently developed methods such as immunocytochemistry or in situ hybridization methods are also but do not obviate the need for tissue specimen. <BR> Numerous non-invasive techniques have also been developed. They include first, the pharmacokinetics of probe drugs known to be metabolised by a particular P-450 or various P-450s. Second, the determination of concentrations of a probe drug and its oxidised metabolite in urine or saliva which in case of genetic polymorphism allows to establish the phenotype o a gicen subject. Third, the determination of the genotype using molecular biology techniques which is increasingly performed for genetic polymorphism. Fourth, the breath test techniques which allow to investigate one CYP family or various CYP enzymes following the administration of a tracer dose of a given compound. Beside these methods which are directly applicable in vivo in each individual, other techniques have been developed to explore drug metabolism in a more direct way. In this field it now appears possible for a given compound to vitro models such as microsomes, hepatocytes in culture, liver slices and cDNA-expression of human cytochrome P-450 in yeast, COS cells or eucaryote cells. These in vitro techniques are particularly useful to predict the potential of drug interactions which may occur in vivo. <BR> Genetic control and drug administration are two main factors modulating the level of CYP activities. Among CYP, two enzymes (CYP2D6 and 2C19) which metabolise more than 50 drugs are regulated by a genetic polymorphism. Such particularity has major clinical consequences in the use of cardiovascular drugs, drugs used for the treatment of psychiatric disorders and in that of codeine. A genetic polymorphism however not confirmed until now has also been suggested for CYP3A which is the most important family in drug metabolism. In this family and in the absence of definitively demonstrated genetic polymorphism a wide variation in activity is observed between individuals. This may explain why it is particularly difficult for the clinician to prescribe the most appropriate dose of a drug metabolised by CYP3A. <BR> Nongenetic factors also contribute to intra- and interpatient differences in the level of CYP activities. Aming these factors, drug administration may induce, inhibit or exert a competitive inhibition on the level of CYP activities. These effects may modify drug metabolism by a factor of then or even more. <BR> The level of CYP activities may also have an impact on the susceptibility of appearance of liver diseases and on the contrary, be modulated by various liver diseases. For example, the appearance of several drugs’ hepatotoxicities is directly modulated by CYP activities. Liver diseases are generally associated with a reduction on liver function which is the net result of multiple factors, among whom cell dysfunction and portal-systemic shunting. Despite the difficulties to evaluate the role of each individual factor, it has been clearly shown that liver function modulates CYP activities. <BR> The studies described in this work have shown the compecity of the cytochrome P-450 system but also its impact on drug metabolism. In the future the establishment for each individual of a CYP “identity card” will constitute the ultimate goal of research in this field. It might allow to characterise the metabolic capacity of each given human being and thus determine the most appropriate dose regimen to be given in each instance. This will reduce both the risk of given a too small dose of a drug (absence of effect) or that related to the administration of a too large dose of a drug (potential toxic effect). This approach might also be helpful in limiting the risk of interaction between drugs and even in modulating in an “artificial” way the activity of some cytochrome P-450 enzymes
- Affiliations
Citations
Horsmans, Y. (1996). Role and modulation of major cytochrome P-450 families in health and liver diseases. https://hdl.handle.net/2078.5/111365