Cytochrome P450's pharmacogenetics in drug development and clinical aspects [review]

cytochrome P450s [CYPs] are members associated heme protein and hepatic microsomal enzymes, which play important role in drugs metabolism and detoxification. Seven of the 57 known human isoforms of P450s responsible for metabolism of more than 90% of the currently used drugs, CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Some. of them, CYP2D6, CYP2C9 and CYP2C19, have been shown to be polymorphic as a result of single nuclcotide polymorphisms [SNPs], gene deletions, and gene duplications. The effect of the polymorphisms ranges from a complete loss of functional protein to an increase in enzyme activity and can impact the drug development and clinical application. Most pharmaceutical companies have increasingly screened out compounds that are metabolized solely by polymorphic CYPs. Retrospective studies showed that one of the major causes of the new chemical entities [NCE] failure to reach the clinical stage was related to pharmacokinetic and toxicological issues. Therefore the industry has invested in the science and technology of absorption, distribution, metabolism, excretion and toxicity [ADMET] in order to reduce NCE attribution rates.. Drug metabolism is the most important determinant of the ADMET of most compounds and the role CYP450 is predominant. Overall, current trends in the industry have been fueled by increased managed healthcare, the desire to minimize the need for therapeutic drug monitoring and CYP genotyping in medical practice, and a very competitive marketplace

Angiotensin II-induced renal vasodilation mediated by cytochrome P-450 arachidonic acid metabolites

Activation of AT2 angiotensin II receptor release cytochrome P-450 arachidonic acid metabolites [CYP-AA]. The presence of the AT2 receptor and its ability to mediate renal vasodilation through CYP-AA metabolites were evaluated. Vascular response to angiotensin II in the isolated perfused kidney of the rat was evaluated in the absence and presence of angiotensin II AT1 and AT2 receptor blockers. Blockade of the AT1 receptor unmasked a vasodilatory response that was inhibited by AT2 receptor blockade and AA metabolism. The findings indicate that blockade of the AT1 angiotensin II receptor, activation of AT2 receptors, releases CYP-AA metabolites that induce renal vasodilation

Kinetics of two cytochrome P450-dependent aromatic amine hydroxylases from lung and liver microsomes of rabbit

The kinetics of 2-aminofluorene [AF] and 4-Aminobiphenyl [4-AB] N-hydroxylase reactions were determined using eight highly purified forms of rabbit liver cytochrome-P450 [Cyt-P450], with control and 2,3,7,8-tetrchloro-dibenzo-p-dioxin [TCDD] induced rabbit lung and liver microsomes.Both AF and 4-AB N-hydroxylases were best defined by two enzymatic systems, showing a high affinity and low capacity and a low affinity; high capacity system in control and TCDD pretreated microsomes. TCDD pretreatment differently modifies the apparent Km and Vmax. of the arylmine N-hydroxylases in the two tissues microsomal enzymes and in a substrate-dependent manner. Cyt-P450 [form 4] showed the following AF N-hydroxylase activity: 3417 +/- 326 pmol N-OH-AF/nmol Cyt-450/min. In contrast to the microsomal situation, the kinetics studies of AF and 4-AB N-hydroxylases with the form 4, were best described by one enzymatic system.