Drugs impact on CYP-450 enzyme family: A pharmacogenetical study of response variation.

Pharmacogenetics is the study of genetic basis in the individual response to drugs. A thorough knowledge of this will lead to a future where tailor-made drugs, suiting an individual, can be used. Scandinavian countries have been known for wide usage of pharmacogenetics and the most widely used application is for genotyping CYP2D6 in treating psychiatric illness. The CYP-450 enzyme, a super family of microsomal drug-metabolizing enzymes, is the most important of enzymes that catalyzes phase-I drug metabolism reaction. CYP2D6 is a member of this family and it has been most intensively studied and the best example of pharmacogenetics variation in drug metabolism. Neuro-transmitter and drug acting CNS viz. codeine, dextromethorphan, metoprolol and tryptyline etc. are well metabolized by this enzyme. Thus, CYP2D6 is one of the most important and responsible enzymes which regulates bioavailability and metabolism of drug. Presently 75 alleles of CYP2D6 have been described which are responsible for variance of metabolism and toxicity of drugs. Thus, by determining variance of CYP2D6 using molecular approaches viz., PCR, real-time PCR, DNA micro-array and molecular docking can determine the adverse effects, drug toxicity, bioavailability and therapeutic potential of new drug.

The effect of lead bioaccumulation on haem biosynthetic enzymes in fish.

The bioaccumulations of lead in the liver and hepatic microsomes of fish after 1, 3, 7, 14, 28, and 45 days exposure were studied. In addition, the relationship between the bioaccumulated lead in both hepatic microsomes and the liver and their haem biosynthetic enzymes were studied. Lead toxicity was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal cytochrome P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. The activity of the heam biosynthetic enzymes delta-aminolevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. The activity of the haem catabolic enzyme, haem oxygenase, was increased by concentration and length of time to lead exposure.

Gender differences in the metabolism of benzene, toluene and trichloroethylene in rat with special reference to certain biochemical parameters.

Metabolites viz. phenol, hippuric acid and total trichloro compounds of benzene, toluene and trichloroethylene respectively were estimated in the urine samples of male and female rats after exposure for a period of 30 days. The results exhibited higher metabolism in female rats than the male rats. Their metabolism might be regulated by cytochrome P450 isozymes in a gender specific manner. However, sex differences in the activity of glutathione-S-transferases of the liver have also been found to determine their toxicity. Results have been discussed with quantitative profiles of other enzymes established in the liver of male and female rats.

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

O papel do citocromo P450 nas interações farmacológicas entre antidepressivos / The role of cytochrome P450 on antidepressants drug interaction

Foi realizada uma revisão bibliográfica sobre interações farmacológicas entre antidepressivos e o papel do CYP. O sistema citocromo P450 ( cerca de 30 enzimas oxidativas agrupadas em 11 grandes famílias é o componente fundamental no metabolismo hepático dos diversos fármacos. A polifarmacoterapia, prática frequente nos ambulátórios psiquiátricos, eleva o risco de interações medicamentosas; estas podendo ser farmacocinéticos e farmacodinâmicas. Dentre as interações farmacocinéticas, as que envolvem o citocromo P450(CYP) apresentam dois princípios: a indução e a inibição enzimáticas. Tais mecanismos participam do metabolismo de diferentes substâncias, inclusive dos antidepressivos, influenciando significativamente a prática clínica, promovendo toxicidade ou falta de eficácia