Current Drug Metabolism

EDITOR’S CHOICE – Inter-individual Variability in Activity of the Major Drug Metabolizing Enzymes in Liver Homogenates of 20 Individuals

Author(s): Shalenie P. den Braver-Sewradj, Michiel W. den Braver, Marc van Dijk, Yongjie Zhang, Stefan J. Dekker, Lukas Wijaya, Nico P.E. Vermeulen, Lysiane Richert, Jan N.M. Commandeur, J. Chris Vos*

Graphical Abstract:

Abstract:

Background: Inter-individual variability in hepatic drug metabolizing enzyme (DME) activity is a major contributor to heterogeneity in drug clearance and safety. Accurate data on expression levels and activities of DMEs is an important prerequisite for in vitro-in vivo extrapolation and in silico based predictions. Characterization and assessment of inter-correlations of the major DMEs cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) have been extensively documented, but simultaneous quantification including other major DMEs has been lacking.

Objective: Assessment of inter-donor variability and inter-correlations of CYPs, UGTs, sulfotransferases (SULTs), glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) in a set of 20 individual liver homogenates.

Method: The main drug metabolizing isoforms of CYP and UGT have been reaction phenotype in individual liver microsomes and NQO1, NQO2, GSTT1 and GSTT2 in corresponding cytosol. In addition, we assessed overall SULT activity in liver cytosol using acetaminophen and 7-hydroxycoumarin as non-selective substrates and cytosolic GST activity using the non-selective substrate 1-chloro-2,4-dinitrobenzene (CDNB). Expression of GST isoforms was also assessed.

Results and Conclusion: While hepatic NQO1 activity was highly variable, NQO2 activity was more conserved. In addition, we found that of the hepatic GST isoforms, the variation in GSTM3 levels, which is poorly studied, was highest. The majority of significant correlations were found amongst CYP and UGT enzyme activities. The dataset presented provides the absolute quantification of the largest number of hepatic DME activities so far and constitute an essential resource for in silico toxicokinetic and metabolic modelling studies.

Read more here: http://www.eurekaselect.com/158885/article

16 May 2018

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27 Feb 2018

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EDITOR’S CHOICE – Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery – Current Drug Metabolism

Journal: Current Drug Metabolism

Author(s): Ogheneochukome Lolodi, Yue-Ming Wang, William C. Wright, Taosheng Chen*

Graphical Abstract:

Abstract:

Background: Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes.

Methods: We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5.

Results: Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands.

Conclusion: Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.

Read more here: http://www.eurekaselect.com/152811

22 Feb 201827 Feb 2018

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BENTHAM SCIENCE PARTNERS WITH ISSX

The International Society for the Study of Xenobiotics (ISSX) signs agreement with Bentham Science Publishers to promote the journals, Current Drug Metabolism and Drug Metabolism Letters, among its members. ISSX is the premier scientific organization for researchers interested in the metabolism and disposition of xenobiotics.

Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of timely review articles and guest edited issues in drug metabolism. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.

Drug Metabolism Letters publishes letters, original research articles, mini-reviews, thematic issues based on mini-reviews and letters, commentaries, technical notes and drug clinical trial studies on major advances in all areas of drug metabolism and disposition.