Publications by authors named "Shenzhi Zhou"

7 Publications

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Glutathione conjugation and protein modification resulting from metabolic activation of venlafaxine and .

Xenobiotica 2021 Jun 23:1-39. Epub 2021 Jun 23.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF.One glutathione (GSH) conjugate and one cysteine conjugate were both detected in mouse and human liver microsomal incubations containing VLF and GSH or cysteine. The two conjugates were also detected in cultured mouse primary hepatocytes and bile of rats after exposure to VLF. The and studies demonstrated that VLF was metabolized to a quinone methide intermediate reactive to GSH and cysteine residues of hepatic protein. The observed protein covalent binding revealed dose-dependency. The metabolic activation of VLF was P450-dependent, and CYP3A4 was found as the predominant enzyme involved in the bioactivation process.These findings facilitate better understanding of the metabolic activation-hepatotoxicity relationship of VLF and provide chemists with information about new potential structural alerts during drug design process.
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http://dx.doi.org/10.1080/00498254.2021.1946204DOI Listing
June 2021

Metabolic Activation of Aegeline Mediated by CYP2C19.

Xenobiotica 2021 Apr 23:1-38. Epub 2021 Apr 23.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

1. Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant , with multiple pharmacological activities.2. As one component of several dietary supplements, AGL caused a series of acute and chronic liver injuries. Nevertheless, the mechanisms of AGL-induced hepatotoxicity remain unclear. This study was conducted to identify reactive metabolite(s), to determine related metabolic pathways, and define the possible association of the bioactivation with AGL cytotoxicity.3. A demethylation metabolite (M1) and a GSH conjugate (M2) were detected in rat liver microsomal incubations containing AGL and GSH. The two metabolites were both found in bile of rats and rat primary hepatocytes after AGL administration.4. Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalyzing this metabolic activation.5. Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of AGL. The results suggest that AGL was metabolized to a -quinone methide intermediate which could in part participate in AGL-induced cytotoxicity.
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http://dx.doi.org/10.1080/00498254.2021.1913666DOI Listing
April 2021

Metabolic Activation of Pirfenidone Mediated by Cytochrome P450s and Sulfotransferases.

J Med Chem 2020 08 18;63(15):8059-8068. Epub 2020 Jul 18.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis. Idiosyncratic drug reactions, due to clinical application of pirfenidone, have been documented, even along with death cases resulting from acute liver failure. The present study aimed at the investigation of metabolic activation of pirfenidone possibly participating in the reported adverse reactions. Pirfenidone-derived glutathione/-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary hepatocyte incubations after exposure to pirfenidone. The GSH/NAC conjugates were also observed in bile and urine of rats given pirfenidone, respectively. The observation of the conjugates suggests the formation of a quinone methide intermediate derived from pirfenidone. The intermediate was possibly generated through two pathways. First, pirfenidone was directly metabolized to the quinone methide intermediate via dehydrogenation; second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed by sulfation to a benzyl alcohol-sulfate derivative. The findings facilitate the understanding of the mechanisms of pirfenidone-induced idiosyncratic toxicity and assist medicinal chemists to minimize toxicities in the development of new pharmaceutical agents.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02073DOI Listing
August 2020

Evidence for Polyamine, Biogenic Amine, and Amino Acid Adduction Resulting from Metabolic Activation of Diosbulbin B.

Chem Res Toxicol 2020 07 22;33(7):1761-1769. Epub 2020 Jun 22.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.

L. (DBL), a traditional Chinese medicine, is a well-known herb with hepatotoxicity, and the biochemical mechanisms of the toxic action remain unknown. Diosbulbin B (DSB), a major component of DBL, can induce severer liver injury which requires cytochrome P450-catalyzed oxidation of the furan ring. It is reported that a -enedial reactive intermediate resulting from metabolic activation of DSB can react with thiols and amines to form pyrrole or pyrroline derivatives. In this study, we investigated the interaction of the reactive intermediate with polyamines, biogenic amines, and amino acids involved in the polyamine metabolic pathway, including putrescine, spermidine, spermine, histamine, arginine, ornithine, lysine, glutamine, and asparagine. Seven DSB-derived amine adducts were detected in microsomal incubations supplemented with DSB and individual amines. Six adducts were observed in cultured rat primary hepatocytes after exposure to DSB. DSB was found to induce apoptosis and cell death in time- and concentration-dependent manners. Apparently, the observed apoptosis was associated with the detected amine adduction. The findings facilitate the understanding of the mechanisms of toxic action of DSB.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00017DOI Listing
July 2020

Immunochemical Detection of Protein Modification Derived from Metabolic Activation of 8-Epidiosbulbin E Acetate.

Chem Res Toxicol 2020 07 11;33(7):1752-1760. Epub 2020 May 11.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Furanoid 8-epidiosbulbin E acetate (EEA) is one of the most abundant diterpenoid lactones in herbal medicine L. (DB). Our early work proved that EEA could be metabolized to EEA-derived -enedial (EDE), a reactive intermediate, which is required for the hepatotoxicity observed in experimental animals exposed to EEA. Also, we found that EDE could modify hepatic protein by reaction with thiol groups and/or primary amines of protein. The present study was inclined to develop polyclonal antibodies to detect protein modified by EDE. An immunogen was prepared by reaction of EDE with keyhole limpet hemocyanin (KLH), and polyclonal antibodies were raised in rabbits immunized with the immunogen. Antisera collected from the immunized rabbits demonstrated high titers evaluated by enzyme-linked immunosorbent assays (ELISAs). Immunoblot analysis showed that the polyclonal antibodies recognized EDE-modified bovine serum albumin (BSA) in a hapten load-dependent manner but did not cross-react with native BSA. Competitive inhibition experiments elicited high selectivity of the antibodies toward EDE-modified BSA. The antibodies allowed us to detect and enrich EDE-modified protein in liver homogenates obtained from EEA-treated mice. The developed immunoprecipitation technique, along with mass spectrometry, enabled us to succeed in identifying multiple hepatic proteins of animals given EEA. We have successfully developed polyclonal antibodies with the ability to recognize EDE-derived protein adducts, which is a unique tool for us to define the mechanisms of toxic action of EEA.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00016DOI Listing
July 2020

Nitidine Chloride Is a Mechanism-Based Inactivator of CYP2D6.

Drug Metab Dispos 2018 08 17;46(8):1137-1145. Epub 2018 May 17.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China (X.M., Z.H., Q.W., N.Z., S.Z., Y.P., J.Z.); State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province and Guizhou Medical University, Guiyang, Guizhou, P. R. China (J.Z.)

Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of (Roxb.) DC, a widely used traditional herbal medicine. Several reports have revealed NC's multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after a 15-minute incubation with NC at 100 M in the primary incubation mixtures, with of 4.36 M, of 0.052 minute, and a partition ratio of approximately 290. Moreover, the loss of CYP2D6 activity required the presence of NADPH. Superoxide dismutase/catalase and glutathione showed minor protection against the NC-induced enzyme inhibition. Quinidine as a competitive inhibitor of CYP2D6 slowed down the inactivation by NC. Trapping experiments using -acetylcysteine demonstrated that quinone and/or carbene intermediate(s) were/was generated in human liver microsomal incubations with NC. In addition, potassium ferricyanide prevented the enzyme from the inactivation mediated by NC, which provided evidence that inhibition of CYP2D6 resulted from heme destruction by the formation of a carbene-iron complex. CYP1A2 was found to be the major enzyme involved in the generation of NC quinone metabolites. In conclusion, NC is a mechanism-based inactivator of CYP2D6. The generation of a carbene intermediate might be mainly responsible for the enzyme inactivation.
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http://dx.doi.org/10.1124/dmd.117.079780DOI Listing
August 2018

Development of Polyclonal Antibodies for Detection of Diosbulbin B-Derived cis-Enedial Protein Adducts.

Chem Res Toxicol 2018 04 29;31(4):231-237. Epub 2018 Mar 29.

Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P. R. China.

Diosbulbin B (DSB), a major component of herbal medicine Dioscorea bulbifera L. (DB), can be metabolized to an electrophilic intermediate, DSB-derived cis-enedial (DDE). DDE was suggested to contribute to the hepatotoxicity observed in experimental animals and humans after their exposure to DSB. Our previous work found that DDE reacted with primary amino and/or sulfhydryl groups of hepatic protein. The objective of the study was to develop polyclonal antibodies that can recognize DDE-derived protein adducts. Immunogens synthesized from DDE and keyhole limpet hemocyanin were employed to raise polyclonal antibodies in rabbits. An enzyme-linked immunosorbent assay (ELISA) demonstrated high titers of antisera obtained from immunized rabbits. Immunoblot analysis showed that DDE-modified bovine serum albumin (BSA) was recognized by the obtained polyclonal antibodies in a concentration-dependent manner and without cross-reaction to native BSA. Competitive ELISA and competitive immunoblot analyses defined the specificity of the antibodies to recognize BSA modified by DDE. Immunoblot analysis also detected a multitude of chemiluminescent bands with a variety of molecular weights in liver homogenates that were harvested from mice treated with DSB. In summary, we have successfully raised polyclonal antibodies to detect protein adducts derived from DDE.
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http://dx.doi.org/10.1021/acs.chemrestox.7b00299DOI Listing
April 2018
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