Interactions of drug-metabolizing enzymes with the Chinese herb Psoraleae Fructus

Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions(HDI) or herb-endobiotic interactions(HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus;the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes(DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.

Cytochrome P450 enzymes mediated by DNA methylation is involved in deoxynivalenol-induced hepatoxicity in piglets

Deoxynivalenol(DON)is an inevitable contaminant in animal feed and can lead to liver damage,then decreasing appetite and causing growth retardation in piglets.Although many molecular mechanisms are related to hepatoxicity caused by DON,few studies have been done on cytochrome P450(CYP450)enzymes and DNA methylation.To explore the role of CYP450 enzymes and DNA methylation in DONinduced liver injury,male piglets were fed a control diet,or diet containing 1.0 or 3.0 mg/kg DON for 4 weeks.DON significantly raised the activity of aspartate aminotransferase(AST),alanine aminotransferase(ALT),and glutamyl transpeptidase(GGT)(P<0.01),leading to liver injury.In vivo study found that DON exposure increased the expression of CYP450 enzymes(such as CYP1A1,CYP2E1,CYP3A29)(P<0.05),and disturbed the expression of nicotinamide N-methyltransferase(NNMT),galanin-like peptide(GALP)and insulin-like growth factor 1(IGF-1)(P<0.05),in which DNA methylation affected the expression of these genes.In vitro study(human normal hepatocytes L02)further proved that DON elevated the expression of CYP1A1,CYP2E1 and CYP3A4(P<0.05),and inhibited cell growth in a dose-dependent manner,resulting in cell necrosis.More importantly,knockdown of CYP1A1 or CYP2E1 could alleviate DON-induced growth inhibition by promoting IGF-1 expression.Taken together,increased CYP450 enzymes expression was one of the mechanisms of hepatoxicity and growth inhibition induced by DON,suggesting that the decrease of CYP450 enzymes can antagonize the hepatoxicity in animals,which provides some value for animal feed safety.

Regulation of the homeostasis of hepatic endoplasmic reticulum and cytochrome P450 enzymes by autophagy

The endoplasmic reticulum(ER)is an intracellular organelle consisting of a continuous network of membranes.In the liver,the ER is highly active in protein modification,lipid metabolism,and xenobiotic detoxification.Maintaining these complicated processes requires elaborate control of the ER lumen environment as well as the ER volume.Increasing evidence suggests that autophagy plays a critical role in regulating the homeostasis of hepatic ER contents and levels of cytochrome P450(CYP)enzymes via selective ER-phagy.This review will provide an overview of ER-phagy,summarizing the possible roles of recently identified ER-phagy receptor proteins in regulating the homeostasis of hepatic ER and CYP enzymes as well as outlining the various implications of ER-phagy in ER-related liver diseases.

Multistage defense response of microalgae exposed to pharmaceuticals in wastewater

Recently, the use of microalgae for bioremediation of pharmaceuticals(Ph As) has attracted increasing interest. However, most studies focused more on microalgae removal performance, its defensive response to the Ph As during wastewater treatment remains unexplored. Herein, microalgal three defensive systems have been investigated in synthetic wastewater, with six Ph As as the typical drug. Results show that Ph As could bind to EPS, and this action in turn could help to alleviate the direct toxicity of Ph As to microalgae. Subsequently, the physiological analyses revealed the increase of superoxide dismutase(SOD), catalase(CAT), and peroxidase(POD) activities, potentially reducing the oxidative stress induced by Ph As. Furthermore, the enzyme activities of cytochrome P450(CYP450) and glutathione-S-transferase(GST) were significantly upregulated after exposure to SMX, CIP and BPA, followed by a significant decrease in biodegradation rates after the addition of CYP450 inhibitors, suggesting that the biotransformation and detoxification of Ph As occurred. Meanwhile, molecular docking further revealed that CYP450 could bind with Ph As via hydrogen bond and hydrophobic interaction, which proved their abilities to be metabolized and form transformation products in microalgae. These findings provide an advancing understanding of microalgae technologies to improve the treatment of wastewater contaminated with Ph As.

Effects of pentachlorophenol on the detoxification system in white-rumped munia(Lonchura striata)

Pentachlorophenol（PCP）, a priority pollutant due to its persistence and high toxicity, has been used worldwide as a pesticide and biocide. To understand the adverse effects of PCP, adult male white-rumped munias（Lonchura striata） were orally administrated commercial PCP mixed with corn oil at dosages of 0, 0.05, 0.5, and 5 mg/（kg·day） for 42 day. Gas chromatography–mass spectrometry（GC–MS） analysis found that PCP was preferentially accumulated in the kidney rather than in the liver and muscle in all exposure groups. To examine the function of CYP1A in pollutant metabolism, we isolated two full-length cDNA fragments（designated as CYP1A4 and CYP1A5） from L. striata liver using reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. PCP induced the expression of CYP1A5, although no obvious change was observed in CYP1A4 expression. Furthermore, PCP significantly elevated the activities of ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase and decreased the activity of benzyloxy-trifluoromethyl-coumarin, with no significant responses observed in benzyloxyresorufin O-debenzylase. PCP induced significant changes in antioxidant enzyme（superoxide dismutase and catalase） activities and malondialdehyde content, but decreased glutathione peroxidase（GSH-Px） and glutathione S-transferase activities and GSH content in the liver of L. striata. The present study demonstrated that PCP had hepatic toxic effects by affecting CYP1As and anti-oxidative status.