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.

[Imidazole-containig drugs and inhibition of cytochrome P450]

Nowadays, multi-medicament use is increasing in clinical practice, especially, in the treatment of elder patients. Therefore, the pharmacokinetic drug-drug interaction of medicaments, which are expected to be co administrated in clinical practice, seems to be significant. The present review provides an update for the relationship between type of chemical substitution [aliphatic or aromatic] of imdazole-containig drugs and their tendency to affect hepatic metabolizing enzyme cytochrome [CYP450s]. In the present review, examples of different therapeutically used imidazole-containing drugs are highlighted to support the first evidence regarding the relationship between CYP-inhibition and chemistry of imidazole ring system. The informations provided throughout this article are intended to improve the medicinal chemist's knowledge of imidazole-containig drugs that are therapeutically widely applied as agents including histamine H1 receptor antagonists [antiallergics], histamine H2 receptor antagonists [antiulcers], histamine H3 receptor antagonists [management of cognitive disorders and attention-deficit-hyperactivity-disorder], antivirals, antiHIV, antibacterials, antifungals, anethelmintics, antiemetics, and antihypertensives

Effect of zinc on hepatic tumor necrosis factor-alpha, cytochrome P450 and antioxidant status of alcohol fed male rats

Alcohol consumption is associated with increased incidence of variety of illnesses including liver cirrhosis and cancers. Studies have shown that ethanol consumption may result in increased some cytokines such as tumor necrosis factor-alpha [TNF-alpha], oxidative stress with increased formation of lipid peroxides and free radicals. Zinc has been shown to have antioxidant actions. This study was carried out to investigate the hepatoprotective and antioxidant properties of zinc using acute and chronic ethanol intoxication as a model of hepatotoxic and oxidative damage. Therefore we studied the effect of zinc on TNF-alpha, cytochrome p450, serum and hepatic enzymes. Also the acute phase protein, C-reactive protein [CRP], was measured to assess the inflammatory activity. Sixty four male rats were assigned to the following groups: control, ethanol fed group, received 3ml of 35% ethanol/rat/day; zinc treated, received 5 mg/kg zinc sulphate solution subcutaneously/ day; alcohol plus zinc group, received zinc pretreatment, 3 days before beginning of ethanol, in the same doses daily for either one or eight weeks. At the end of each period half of each group were sacrificed, blood sample were collected for determination of ALT, total bilirubin, alkaline phosphatase [ALP] and CRP in the sera; while glutathione peroxidase [GPX], superoxide dismutase [SOD], malondialdehyde [MDA],CYP 450 and TNF-alpha were determined in liver homogenates. Ethanol administration caused significant elevation of serum ALT, ALP, CRP, and hepatic MDA, CYP 450 and TNF-alpha after one and eight weeks. While serum total bilirubin increased significantly only after 8 weeks. On the other hand ethanol feeding caused significant reduction of hepatic GPX and SOD after one and eight weeks compared to control rats. Zinc administration to ethanol fed rats could reduce all serum enzymes and hepatic MDA and CYP 450 significantly after one and eight weeks and TNF-alpha after one week only compared to ethanol fed rats, to reach insignificant differences with control values except for CRP and TNF-alpha. CYP 450 activity was correlated to the degree of lipid peroxidation and oxidative stress as indicated by the MDA levels. we concluded that, the higher levels of total bilirubin and ALP in chronic alcohol intoxication might reflect the beginning of liver cirrhosis; together with serial measurement of CRP appear to be useful indices in assessing the clinical activity of chronic alcohol intoxication, as these conventional tests are widely available and relatively inexpensive. CYP 450 activity is correlated to the degree of alcohol induced oxidative stress. Also we concluded that zinc could reduce the elevated TNF-alpha and has antioxidant effects, as it could normalize the hazardous CYP 450 and MDA levels. Therefore it can protect the liver from alcohol induced hepatic injury specially the acute form

Effect of rifampicin & isoniazid on cytochrome P-450 in mycobacteria.

BACKGROUND & OBJECTIVES: Rifampicin and isoniazid are the most important first line drugs used in the treatment of tuberculosis. These drugs are also used in combination with other medications to treat co-infections. It, therefore, becomes important to study the effect of these drugs on the drug metabolizing system, namely, cytochrome P-450, not only in the host but also in the bacteria. We report the effect of rifampicin and isoniazid on the cytochrome P-450 activity in Mycobacterium smegmatis and M. tuberculosis H37Rv. METHODS: Subinhibitory concentrations of rifampicin and isoniazid were added to the organisms after they had attained the growth phase and cytochrome P-450 activity was estimated in the membranous fractions of the bacteria at different time points. RESULTS: Rifampicin was able to significantly enhance cytochrome P-450 in both M. smegmatis and M. tuberculosis H37Rv. Isoniazid was found to inhibit cytochrome P-450 in M. tuberculosis H37Rv, while there seemed to be no effect in M. smegmatis. INTERPRETATION & CONCLUSION: We report here the effect of rifampicin and isoniazid on mycobacterial cytochrome P-450. These findings are similar to those found in eukaryotic organisms. The role of mycobacterial cytochrome P-450 in the metabolism of drugs within the bacteria needs to be elucidated.

Interaçöes entre a Nefazodona e o Sistema Citocromo P450 / Interactions between nefazodone and CYP-450

Este estudo com a nefazodona, um novo inibidor seletivo de recaptaçäo de serotonina(ISRS), tem o objetivo maior de mostrar o perfil de interaçöes medicamentosas, droga com droga, assim como com o CYP-450, mostrando os principais efeitos colaterais e açöes terapêuticas principais

Aspectos moleculares de la resistencia a insecticidas / Molecular basic of insecticide resistance

El surgimiento de resistencia en poblaciones de insectos es uno de los efectos indeseables asociados al uso de insecticidas, y es un buen ejemplo del modo en que ocurren los procesos microevolutivos. En 1908 se documentó por primera vez la existencia de insectos resistentes a insecticidas. Ahora se conocen casos de resistencia en más de 500 especies de artrópodos. Los principales mecanismos que confieren resistencia a insecticidas son penetración cuticular reducida, metabolismo degradativo aumentado y reducción en la susceptibilidad de los sitios de acción. Los métodos de la biología molecular permiten identificar las bases moleculares de esos mecanismos. El propósito de este artículo es reseñar el conocimiento disponible acerca de la biología molecular de la resistencia a insecticidas: mutaciones puntuales en genes de acetilcolinesterasa (Drosophila melanogaster) y del receptor de GABA (varias especies), inserciones en genes de transferasas (D. melanogaster) y del citocromo P450 (D. melanogaster), amplificación de genes de esterasas (Myzus persicae y Culex pipiens / quinquefasciatus complex), cambios que afectan la expresión del gen del citocromo P450 (Musca domestica), y una mutación ligada al gen del canal de sodio dependiente de voltaje (M. domestica)

Interaçöes medicamentosas: Antidepressivos novos e o sistema citocromo P450 / Drug interactions: Newer antidepressants and the cytochrome P450 system

A maioria dos fármacos sofre biotransformaçäo, frequentemente envolvendo a oxidaçäo no fígado. Recentemente, descobriu-se que algumas enzimas do sistema enzimático citocromo P450 säo responsáveis pelos primeiros passos metabólicos d maioria dos fármacos. Algumas drogas podem inibir enzimas P450 e esta inibiçäo pode levar a interaçöes potenciais com outros fármacos. Muitos estudos têm focalizado o sistema citocromo P450 e seu papel em interaçöes medicamentosas potnciais. Este artigo apresenta as evidências in vitro e in vivo da inibiçäo de enzimas do sistema citocromo P450 (1A2, 2C9, 2C19, 2D6, 3A3/4) por antidepressivos recentemente introduzidos no mercado (citalopram, fluoxetina, fluvoxamina, nefazodona, paroxetina, sertralina e venlafaxetina) e sua relevância clínica potncial

Trypanocidal effect of SKF525A, proadifen, on different developmental forms of Trypanosoma cruzi

SKF525A, an inhibitor and inducer of cytochrome P450, was tested on different developmental stages of Trypanosoma cruzi. Growth, motility and structure of epimastigotes, motility and infectivity of trypomastigotes, and infectivity of trypomastigotes to Vero cells in culture were abolished by the drug at 10-100 muM concentration. When blood from infected mice was treated with the drug, and used to infect 8 day-old-mice, no parasites were observed at 0.6-1 mM, and all animals survived. Blood cell morphology was well preserved, and the sleeping time of pentobarbital-treated mice inoculated with the same amount of drug was not increased. The present results suggest that SKF525A or other related inhibitors of cytochrome P450 coned be tested as an additive for blood sterilization in blood banks.

Effect of country liquor (Indian alcoholic beverage) on carcinogen activating and detoxifying enzymes.

The levels of some important drug activating and detoxyfying enzymes were estimated in the livers of Swiss mice treated with a local brand of country liquor. Following liquor ingestion in male mice elevated levels of hepatic cytochrome P-450 were observed, while female mice did not show this. Cytochrome b5 levels remained unchanged. Similarly in male mice, increase in hepatic reduced glutathione levels were obtained while in female mice, decrease in this was observed. The activity of glutathione S-transferase was not changed. It is suggested that the increases in cytochrome P-450 and in hepatic reduced glutathione may be important determinants in carcinogenecity of the country liquors.

Comparison between the effect of pyrazole, cobalt and tin on hepatic and renal microsomal cytochrome P450 concentration and metabolism of coumarin and 7 ethoxycoumarin

Recently, the metabolism of coumarin and 7-ethoxycoumarin were reported to be enhanced several folds in the mouse liver after pretreatment with either N-containing heteroaromatic compounds [e.g. pyrazole, PL] or heavy metals [e.g. Cobalt, Co and Tin, Sn]. The effect of these compounds on the mouse renal microsomes is not thoroughly investigated. Accordingly the present study was designed to compare the effect of pyrazole. cobalt and tin on hepatic and renal microsomes. The study revealed that in both kidney and liver microsomes, the concentration of Cyt P450 was decreased to about the same extent after pretreatment of male mice [NMRI-type] with these compounds. In contrary the metabolism of 7-ethoxy-coumarin and of Coumarin were increased several folds. In the liver microsomes, the highest increase in the metabolism of the coumarin derivatives, were observed after pretreatment of mice with Sn [Sn > PL > Co]. On the other hand, in the kidney microsomes, the most potent inducer was found to be PL [PL> Co>Sn]. These results indicate that PL, Co or Sn enhance the hepatic and renal metabolism of coumarin derivatives by different rates. Accordingly, these data suggested the different regulation of the coumarin derivatives metabolizing enzymes in the -liver from that in the kidney