Inter-individual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 Individuals

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

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)370-381
Number of pages12
JournalCurrent Drug Metabolism
Volume19
Issue number4
DOIs
Publication statusE-pub ahead of print - 8 Jan 2018

Fingerprint

Liver
Glucuronosyltransferase
Oxidoreductases
Cytochromes
Glutathione Transferase
Enzyme activity
Enzymes
Pharmaceutical Preparations
NAD
Sulfotransferases
Protein Isoforms
7-hydroxycoumarin
Computer Simulation
Cytosol
Dinitrochlorobenzene
Liver Microsomes
Substrates
Acetaminophen
Extrapolation
benzoquinone

Keywords

  • Journal Article
  • Correlations
  • Drug metabolizing enzymes
  • Inter-individual variability
  • Phase I metabolism
  • Phase II metabolism
  • Reaction phenotyping

Cite this

den Braver-Sewradj, Shalenie P ; den Braver, Michiel W ; van Dijk, Marc ; Zhang, Yongjie ; Dekker, Stefan J ; Wijaya, Lukas ; Vermeulen, Nico P E ; Richert, Lysiane ; Commandeur, Jan N M ; Vos, J Chris. / Inter-individual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 Individuals. In: Current Drug Metabolism. 2018 ; Vol. 19, No. 4. pp. 370-381.
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Inter-individual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 Individuals. / den Braver-Sewradj, Shalenie P; den Braver, Michiel W; van Dijk, Marc; Zhang, Yongjie; Dekker, Stefan J; Wijaya, Lukas; Vermeulen, Nico P E; Richert, Lysiane; Commandeur, Jan N M; Vos, J Chris.

In: Current Drug Metabolism, Vol. 19, No. 4, 08.01.2018, p. 370-381.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Inter-individual variability in activity of the major drug metabolizing enzymes in liver homogenates of 20 Individuals

AU - den Braver-Sewradj, Shalenie P

AU - den Braver, Michiel W

AU - van Dijk, Marc

AU - Zhang, Yongjie

AU - Dekker, Stefan J

AU - Wijaya, Lukas

AU - Vermeulen, Nico P E

AU - Richert, Lysiane

AU - Commandeur, Jan N M

AU - Vos, J Chris

N1 - Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

PY - 2018/1/8

Y1 - 2018/1/8

N2 - 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.

AB - 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.

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KW - Phase I metabolism

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KW - Reaction phenotyping

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