Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 muM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.
Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System* ; Humans ; Hydrolysis ; Metabolism ; Microsomes, Liver ; Proadifen* ; Protein Isoforms

Gukang Capsules are often used in combination with drugs to treat fractures, osteoarthritis, and osteoporosis. Cytochrome P450(CYP450) mainly exists in the liver and participates in the oxidative metabolism of a variety of endogenous and exogenous substances and serves as an important cause of drug-metabolic interactions and adverse reactions. Therefore, it is of great significance to study the effect of Gukang Capsules on the activity and expression of CYP450 for increasing its clinical rational medication and improving the safety of drug combination. In this study, the Cocktail probe method was used to detect the changes in the activities of CYP1A2, CYP3A2, CYP2C11, CYP2C19, CYP2D4, and CYP2E1 in rat liver after treatment with high-, medium-and low-dose Gukang Capsules. The rat liver microsomes were extracted by the calcium chloride method, and protein expression of the above six CYP isoform enzymes was detected by Western blot. The results showed that the low-dose Gukang Capsules could induce CYP3A2 and CYP2D4 in rats, medium-dose Gukang Capsules had no effect on them, and high-dose Gukang Capsules could inhibit them in rats. The high-dose Gukang Capsules did not affect CYP2C11 in rats, but low-and medium-dose Gukang Capsules could induce CYP2C11 in rats. Gukang Capsules could inhibit CYP2C19 in rats and induce CYP1A2 in a dose-independent manner, but did not affect CYP2E1. If Gukang Capsules were co-administered with CYP1A2, CYP2C19, CYP3A2, CYP2C11, and CYP2D4 substrates, the dose should be adjusted to avoid drug interactions.
Rats ; Animals ; Cytochrome P-450 CYP1A2/metabolism* ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 CYP2E1/pharmacology* ; Rats, Sprague-Dawley ; Cytochrome P-450 Enzyme System/metabolism* ; Microsomes, Liver ; Liver ; Cytochrome P-450 CYP3A/metabolism*

Flavonoids are present in fruits, vegetables and beverages derived from plants, and in many dietary supplements or herbal remedies. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction or inhibition of these enzymes. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzyme CYP1, 2E1, 3A4 and 19. Flavonoids alter CYPs by various mechanisms, including the stimulation of gene expression via specific receptors and/or CYP protein, or mRNA stabilization and so on. But in vivo and in vitro, the effects of flavonoids are not always coincident as a result of concentrations of flavonoids, genetic and environmental factors. As well, flavonoids may interact with drugs through the induction or inhibition of their metabolism. Much attention should be paid to the metabolism interaction of the flavonoids when coadministered with other drugs.
Animals ; Aromatase ; genetics ; metabolism ; Cytochrome P-450 CYP1A1 ; antagonists & inhibitors ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 Inhibitors ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Enzyme Activation ; drug effects ; Flavonoids ; pharmacology ; Humans ; RNA, Messenger ; genetics ; metabolism

The regulation mechanism of arecoline on rat hepatic CYP2E1 was studied in vivo. After oral administration of arecoline hydrobromide (AH; 4, 20 and 100 mg x kg(-1) x d(-1)) to rats for one week, the hepatic CYP2E1 mRNA level remained unchanged, but the hepatic CYP2E1 protein content was dose-dependently increased. Additionally, although the hepatic CYP2E1 activity was induced by AH treatment, the induction was attenuated with the increase in dosage. The results indicate that the effect of arecoline on rat hepaticdoes not involve transcriptional activation of the gene, but largely involves the stabilization of CYP2E1 protein against degradation or increased efficiency of CYP2E1 mRNA translation, and additionally involve the post- ranslational modification of CYP2E1 protein. Furthermore, the CYP2E1 response is fairly equal among the different species, the induction of rat hepatic CYP2E1 by arecoline suggests that there is a risk of metabolic interaction among the substrate drugs of CYP2E1 in betel-quid use human.
Animals ; Arecoline ; pharmacology ; Cytochrome P-450 CYP2E1 ; metabolism ; Cytochrome P-450 CYP2E1 Inducers ; pharmacology ; Humans ; Liver ; drug effects ; metabolism ; RNA, Messenger ; Rats

Chlorzoxazone ; blood ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2E1 ; blood ; Humans

Cytochrome P-450 CYP2E1 ; genetics ; Fatty Liver ; enzymology ; genetics ; Female ; Genotype ; Humans ; Male ; Polymorphism, Genetic

The kiwi (Actinidia deliciosa) is well known to contain anti-oxidants. In this study, we investigated the anti-oxidant effects of kiwi extract on carbon tetrachloride (CCl4) induced liver injury in BALB/c mice. The radical scavenging effect of 80% methanol extract of Halla-Gold kiwi was observed. For the animal study, mice were randomly divided into four groups: normal group, CCl4-induced model group, kiwi extract administered group, and silymarin treated group. The kiwi extract was provided daily for 10 days. At the 24 h after last administration, CCl4 was injected. The kiwi extract showed strong inhibitory effect of DPPH radicals and superoxide scavenging. In animal study, administration of CCl4 resulted in significantly elevated plasma levels of ALT and AST but they decreased in kiwi-extract pretreated group. Anti-oxidant enzymes such as GSH-px and GSH-rd were restored in the kiwi extract treatment group. Histopathological degeneration was also prevented in the kiwi extract treated group compared with of the control group, which exhibited CCl4-induced hepatotoxicity. On the basis of the obtained results, it can be concluded that kiwi extract showed protective effects, not only as anti-oxidant effects, but also in the protection of hepatotoxicity in CCl4-intoxicated mice.
Animals ; Antioxidants ; Carbon ; Carbon Tetrachloride ; Cytochrome P-450 CYP2E1 ; Fruit ; Liver ; Methanol ; Mice ; Plasma ; Silymarin ; Superoxides

Animals ; Cytochrome P-450 CYP2E1 ; biosynthesis ; genetics ; Fatty Liver ; genetics ; Liver ; metabolism ; Male ; Rats ; Rats, Wistar

Cytochrome P-450 CYP2E1 ; metabolism ; Fatty Liver, Alcoholic ; enzymology ; pathology ; Liver ; enzymology

The reasons of same site recurrence in fixed drug eruptions (FDEs) remain to be clarified. Although the nature of antigen in FDE is unknown, drug metabolites could play a role for antigen formation. Cytochrome p450 isozymes (CYPs) are important enzymes for drug metabolism. This study was done to examine the role of CYPs in FDEs. Provoked lesion was compared with non-provoked lesion by the same drug on the same patient to overcome inter-individual variations of CYPs. The reverse transcriptase-polymerase chain reaction (RT-PCR) with primers for CYPs and the immunohistochemistry (IHC) with anti-CYPs, pancytokeratin, and leukocyte common antigen (LCA) antibodies were conducted. The causative drugs were different in 13 patients who conducted RT-PCR, and the result could not be analyzed by the cause. The levels of CYP2C8/19 and CYP2E1 mRNAs increased significantly in provoked lesions. The keratinocytes in cases of mefenamic acid-induced FDEs stained strongly with anti-CYP2C9 antibody not with the other three antibodies (CYP1A1, CYP2E1, and CYP3A4). The FDE cases from doxycycline, which is not metabolized by CYP2C9 enzyme, and those from chlormezanone did not react to anti-CYP2C9 antibody. The cells stained with CYP antibodies did not react with anti-LCA antibody but with anti-pancytokeratin antibody. The number of cells which reacted to anti-LCA antibody clearly increased in the provoked lesions, regardless of the cause. The above results suggest that CYPs may contribute the drug antigen formation and different levels of CYPs between provoked and non-provoked lesions can play a role for the same site recurrence of lesions in FDEs.
Antibodies ; Antigens, CD45 ; Chlormezanone ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Doxycycline ; Drug Eruptions ; Humans ; Immunohistochemistry ; Isoenzymes* ; Keratinocytes ; Metabolism ; Recurrence ; RNA, Messenger