Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man

Gibson, G. Gordon; Plant, Nick; Swales, KE; Ayrton, Andrew D.; El-Sankary, Wafaa

doi:10.1080/00498250110102674

Cited by 189 publications

(127 citation statements)

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“…Since human CYP3A4 is responsible for approximately 60% of CYP450-mediated metabolism of drugs in therapeutic use today, with anti-cancer drugs in particular (69,70), this result suggests that kava can potentially affect drug metabolism. Upon metabolism, the kava lactones containing methylenedioxyphenyl group in kava extract inhibited multiple cytochrome P450 enzymes (71)(72)(73)(74)(75).…”

Section: Alteration Of Cytochrome P450 Metabolizing Isozymes-it Has Bmentioning

confidence: 96%

Toxicity of Kava Kava

Xia

Guo

et al. 2008

Journal of Environmental Science and Health, Part C

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Kava is a traditional beverage of various Pacific Basin countries. Kava has been introduced into the mainstream U.S. market principally as an anti-anxiety preparation. The effects of the long-term consumption of kava have not been documented adequately. Preliminary studies suggest possible serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. As such, kava extract was nominated for the chronic tumorigenicity bioassay conducted by the National Toxicology Program (NTP). At present toxicological evaluation of kava extract is being conducted by the NTP. The present review focuses on the recent findings on kava toxicity and the mechanisms by which kava induces hepatotoxicity. KeywordsKava; anti-anxiety herbal beverage; top-selling botanical; hepatotoxicity; metabolism; mechanism Kava, prepared from the rhizome of the kava tropical shrub plant, Piper methysticum Forst F., is a traditional beverage used for many centuries, especially at ceremonial activities in the South Pacific (1-6). During recent years, kava has been used in Europe for treatment of anxiety and nervous disorders such as stress and restlessness, and in the United States as a natural alternative to anti-anxiety drugs and sleeping pills (6). Kava sales totaled more than $ 100 million in 1998, being the fifth leading seller of the North American botanicals (7).The association between the use of kava products and hepatotoxicity has prompted many countries, including Germany, Switzerland, France, Canada, and the United Kingdom, to take regulatory actions, ranging from warning consumers to removing kava-containing products from the marketplace. On March 25, 2002, the Center for Food Safety and Applied Nutrition (CFSAN), U.S. Food and Drug Administration (FDA) issued a Consumer Advisory entitled "Kava-containing dietary supplements may be associated with severe liver injury" to the public (8, 9). Kava-containing products remain popular in the United States and continue to be sold in health food stores and ethnic markets regardless of the fact that it Address correspondence to Peter P. Fu, National Center for Toxicological Research, Jefferson, AR 72079. peter.fu@fda.hhs.gov; chanp@niehs.nih.gov. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript was banned in Germany, France, Switzerland, Australia, and Canada (10). In this review, human exposure and metabolism of kava are briefly addressed, recent findings on the toxicity of kava are reported, and possible mechanisms by which kava induces toxicity are described. CHEMICAL COMPOSITIONThe kava plant, belonging to the Piperacae family, is widely cultivated in the South Pacific.Kava is cultivated for its rootstock. Depending upon the amount of kavalactones contained in the resin, the rootstock shows different color, varying from white to dark yellow (2,5,6). Fresh kava rootstock contains about 80% water. Dried rootstock consists of about 43% starch, 20% fibers, 12% water, 3-4% proteins, 3% sugars, 3% minerals, ...

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Section: Alteration Of Cytochrome P450 Metabolizing Isozymes-it Has Bmentioning

confidence: 96%

Toxicity of Kava Kava

Xia

Guo

et al. 2008

Journal of Environmental Science and Health, Part C

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“…Rat CYP3A2 exhibits a 73% homology to the amino acid sequences of human CYP3A4 (28). The induction of CYP3A2 by carbonated SDs may indicate its potential ability to induce human CYP3A4 due to their close homology (29).…”

Section: Discussionmentioning

confidence: 99%

“…A significant correlation was reported between enzyme activity and mRNA expression for CYP3A4 in human liver samples (30). Rat CYP3A2 and human CYP3A4 are involved in the metabolism of erythromycin, nifedipine, lidocaine, testosterone, aflatoxin B1 and benzo[a]pyrene (28,30). Furthermore, CYP3A4 is highly expressed in the adult liver and small intestine (30), and metabolizes xenobiotics and carcinogens (32,33), as well as numerous endogenous compounds, such as bile acids, cholesterol, prostaglandins, fatty acids, retinoids, leukotrienes and biogenic amines (32,34).…”

Section: Discussionmentioning

confidence: 99%

Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

2016

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Abstract.The aim of the current study was to examine the effects of chronic consumption of soft drinks (SDs) on hepatic oxidative stress and cytochrome P450 enzymes (CYPs) expression in the livers of Wistar rats. For 3 consecutive months, the rats had free access to three different soft drinks, Coca-Cola, Pepsi-Cola and 7-UP. The rats were subsequently compared with control group rats that had consumed water. Blood and hepatic tissue samples were assayed for the changes in antioxidants, liver function biomarkers and hepatic gene expression for different isoforms of hepatic CYP. The results indicated that SD consumption (SDC) decreased serum antioxidant levels and increased malondialdehyde secretion, and increased liver biomarkers (glutamate pyruvate transaminase and glutamate oxaloacetate). SD induced alterations in mRNA expression of hepatic antioxidants and cytochrome isoforms. The expression of peroxidase, catalase, CYP1A2, CYP3A2 and CYP2C11 in the liver were upregulated following SDC. By contrast, CYP2B1 was downregulated after 3 months of SDC in liver tissue samples. Thus, the present findings indicate that SDs induced oxidative stress in the liver of Wistar rats and for the first time, to the best of our knowledge, indicate that SDC disrupts hepatic CYP enzymes that may affect drug metabolism. Therefore, drug-dosing programs should be carefully designed to take these novel findings into consideration for the treatment of diseases.

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“…This is potentially due to low amounts of these enzymes expressed in rat liver (85)(86)(87)(88). Unlike in humans, CYP3As are not the major P450 enzymes in rat liver, and to obtain significant expression of these enzymes, induction by phenobarbital or dexamethasone is typically used.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Protein Targets of the Reactive Metabolite of Teucrin A in Vivo in the Rat

Druckova

Mernaugh

Ham

et al. 2007

Chem. Res. Toxicol.

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Covalent modification of proteins is associated with the toxicity of many electrophiles, and the identification of relevant in vivo protein targets is a desirable but challenging goal. Here, we describe a strategy for the enrichment of adducted proteins utilizing single-chain fragment variable (ScFv) antibodies selected using phage-display technology. Teucrin A is a furan-containing diterpenoid found in the herb germander that is primarily responsible for the herb's hepatotoxicity in rodents and humans following metabolic activation by cytochrome P450 enzymes. Conjugates of the 1,4-enedial derivative of teucrin A, its presumed toxic metabolite, with lysine-and cysteine-containing peptides were synthesized and used to select ScFvs from a rodent phage-displayed library, which recognized the terpenoid moiety of the teucrin-derived adducts. Immunoaffinity isolation of adducted proteins from rat liver homogenates following administration of a toxic dose of teucrin A afforded a family of proteins that were identified by liquid chromatography/tandem mass spectrometry. Of the 46 proteins identified in this study, most were of mitochondrial and endoplasmic reticulum origin. Several cytosolic proteins were found, as well as four peroxisomal and two secreted proteins. Using Ingenuity Pathway Analysis software, two significant networks involving the target genes were identified that had major functions in gene expression, small molecule biochemistry, and cellular function and maintenance. These included proteins involved in lipid, amino acid, and drug metabolism. This study illustrates the utility of chemically synthesized biological conjugates of reactive intermediates and the potential of the phage display technology for the generation of affinity reagents for the isolation of adducted proteins.

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Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man

Cited by 189 publications

References 113 publications

Toxicity of Kava Kava

Toxicity of Kava Kava

Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

Identification of the Protein Targets of the Reactive Metabolite of Teucrin A in Vivo in the Rat

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