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Arachidonic acid (AA) is metabolized by enzymes of the cytochrome P450 (CYP) 4A and CYP4F subfamilies to 20- hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the cardiovascular system. In the current work, we reviewed the formation of 20-HETE in different species by different CYPs; 20-HETE metabolism by cyclooxygenases (COXs) and different isomerases; and the current available inducers and inhibitors of 20-HETE formation in addition to its agonists and antagonists. Moreover we reviewed the negative role of 20-HETE in cardiac hypertrophy, cardiotoxicity, diabetic cardiomyopathy, and in ischemia/reperfusion (I/R) injury. Lastly, we reviewed the role of 20-HETE in different hypertension models such as the renin/angiotensin II model, Goldblatt model, spontaneously hypertensive rat model, androgen-induced model, slat- and deoxycorticosterone acetate (DOCA)-salt-induced models, and high fat diet model. 20-HETE can affect pro- and anti-hypertensive mechanisms dependent upon where, when, and by which isoform it has been produced. In contrast to hypertension we also reviewed the role of 20-HETE in endotoxin-induced hypotension and the natriuretic effects of 20-HETE. Based on the recent studies, 20-HETE production and/or action might be a therapeutic target to protect against the initiation and progression of cardiovascular diseases.

Desethylamiodarone was reported to inactivate human CYP1A1. To assess this, two protocols were implemented employing dilution and non-dilution of the preincubation mixture. Inactivation studies performed with diluted preincubation mixtures showed no inactivation of CYP1A1 by desethylamiodarone. However there was evidence for a mixed competitive inhibition (competitive and the uncompetitive inhibition constants of 2.1 microM and 9.6 microM, respectively) of CYP1A1 by desethylamiodarone. NADPH addition and/or replenishment were found to be important factors in determining the control activity in inactivation studies.

Peganum harmala L. (Zygophyllaceae) is a common plant in Middle East and it is still used traditionally to treat several diseases. The effect of P. harmala extract on the expression of different cytochrome P450's (CYP) involved in drug metabolism was examined in human HepG2 cells. Therefore, HepG2 cells were incubated with increasing concentrations of plant extract and the CYP gene expression was determined by real-time PCR. Our results showed that P. harmala extract significantly increased the expression of CYP1A2, 2C19, and 3A4 whereas; CYP 2B6, 2D6 and 2E1 was significantly decreased. We concluded that care should be taken when P. harmala is co-administered with other drugs.

Nuclear factor kappa B (NF-kappaB) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 (CYP), the most important family of drug metabolizing enzymes. Therefore, in this review, we addressed the potential role of NF-kappaB in CYP regulation. We proposed three mechanisms by which NF-kappaB can regulate CYP expression and activity. First, NF-kappaB can directly regulate the expression of CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7, and CYP27B1 through binding to the promoter region of these genes. Second, NF-kappaB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR. Finally, NF-kappaB can regulate CYP activity at post-transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability. In addition, increased inflammatory mediators, oxidative stress, and subsequent NF-kappaB activation have been demonstrated in many conditions such as inflammatory bowel diseases, rheumatoid arthritis, psychological stress, diabetes, aging, cancer, renal diseases, and congestive heart failure. Meanwhile, there is a significant alteration of CYP expression and activity in these diseases. Therefore, we propose that NF-kappaB could be one of the links between inflammation, oxidative stress, and CYP regulation in these diseases. In conclusion, NF-kappaB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions.

Heart failure is a very serious cardiovascular disease that affects more than five million people in North America. The role of cytochrome P450 (CYP) in cardiovascular health and disease is well established. Many CYP enzymes have been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy and heart failure. There is a great deal of discrepancy between various reports on CYP alterations during heart failure, likely due to differences in disease severity, species in question and other underlying conditions. In general, however, cardiac CYP1B and CYP2A, CYP2B, CYP2E, CYP2J, CYP4A and CYP11 mRNA levels and related enzyme activities are usually increased. Moreover, there is a strong correlation between CYP-mediated endogenous metabolites and the pathogenesis of cardiac hypertrophy and heart failure. Some of these metabolites confer cardioprotective effect such as estradiol, dehydroepiandrosterone, epoxyeicosatrienoic acids, and prostaglandin I(2); whereas, other metabolites may be harmful to the heart such as androgens, aldosterone, hydroxyeicosatetraenoic acids, and thromboxane A(2). On the other hand, heart failure plays an important role in the down-regulation of hepatic CYP involved in drug metabolism through several mechanisms which include hepatocellular damage, hypoxia, elevated levels of pro-inflammatory cytokines, and increased production of heme oxygenase-1. Therefore, more research is needed to elucidate the mechanisms by which CYP affect the development and/or progression of heart failure and also the mechanism by which heart failure alters cardiac and hepatic CYP enzymes.

Tert-butylhydroquinone (tBHQ) has been commonly used as a synthetic food antioxidant to prevent oils and fats from oxidative deterioration and rancidity due to its potent anti-lipid peroxidation activity. In North America, the maximum level of tBHQ allowed in fat products is 0.02% with an acceptable daily intake of 0-0.7 mg/kg body weight. Extensive studies have demonstrated that tBHQ exhibit anti-carcinogenic effect. The ability of tBHQ to induce phase II xenobiotic metabolizing enzymes through an Nrf2-dependent pathway is thought to be responsible for the observed protective effect of tBHQ. It has been proposed that tBHQ enhances Nrf2-mediated transcription by promoting reactive oxygen species-mediated dissociation of Nrf2-Keap1, Nrf2 stabilization, phosphatidylinositol 3-kinase (PI3K)/Akt activity, and MAPK pathway activation. In contrast to the beneficial effects of tBHQ, a number of studies have shown that chronic exposure to tBHQ may induce carcinogenicity. However, the precise mechanisms of tBHQ carcinogenicity are not well understood. The toxicity or carcinogenicity of tBHQ has been attributed to the formation of reactive GSH-conjugates, generation of reactive species, CYP1A1 induction, caspase activation and reduced GSH/ATP levels. This review provides an account of recent mechanisms proposed for both chemoprotective and carcinogenic effect of tBHQ.

Cytochrome P450 (CYP450) enzymes have the capability of playing key metabolic roles in several aspects of cancer as a consequence of their unusually broad substrate specificities. CYP450 are also prominent players in the metabolism of anticancer therapeutic drugs, enhancing or diminishing the efficacy of the drugs depending on whether the drug or its metabolites are efficacious. As CYP450 enzymes are also found in lung tissue, lung metabolism can be of importance to the bioactivation of some anticancer agents. The presence of individual forms of CYP450 has been investigated in lung tumor to determine whether intra-tumor metabolism of anticancer agents by CYP450 could occur and thus influence the response of tumor to these agents. Differences in drug metabolism between normal and cancerous lung tissue have been shown to exist, therefore; the variable expression of CYP450 between tumor and normal tissue can provide a basis for selective sensitivity of tissue to anticancer drugs, thereby localizing drug actions to tumor. This review gives a detailed picture of the expression of CYP450 in lung tumor and the role of this enzyme in lung tumor in the fate of anticancer drugs.

Cirrhosis is the end stage of many forms of liver pathologies including hepatitis. The liver is known for its vital role in the processing of xenobiotics, including drugs and toxic compounds. Cirrhosis causes changes in the architecture of the liver leading to changes in blood flow, protein binding, and drug metabolizing enzymes. Drug metabolizing enzymes are primarily decreased due to loss of liver tissue. However, not all enzyme activities are reduced and some are only altered in specific cases. There is a great deal of discrepancy between various reports on cytochrome p450 alterations in liver cirrhosis, likely due to differences in disease severity and other underlying conditions. In general, however, CYP1A and CYP3A levels and related enzyme activities are usually reduced and CYP2C, CYP2A, and CYP2B are mostly unaltered. Both alcohol dehyrogenases and aldehyde dehydrogenases are altered in liver cirrhosis, although the etiology of the disease may determine the expression of alcohol dehydrogenases. Glucuronidation is mainly preserved, but there are a number of factors that determine whether glucuronidation is affected in patients with liver cirrhosis. Low sulphation rates are usually found in patients with liver disease but a decrease in sulfatase activity compensates for the decrease in sulphation rates. In all cases, a reduction in drug metabolizing enzyme activities in liver cirrhosis contributes to decreased clearance of drugs seen in patients with liver abnormalities. The reduction in drug metabolizing enzyme activity must be taken into consideration when adjusting doses, especially in patients with severe liver disease.