Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Alzeer, Samar; Ellis, Elizabeth M.

doi:10.1016/j.bcp.2014.09.004

Cited by 12 publications

(9 citation statements)

References 45 publications

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“…63 Other results from experiments performed on multiple cell types (including human brain and hepatoma cell lines) support the transformation of accumulated GHB by a dehydrogenase identified as AKR1A1 using short interfering RNA. 64,65 This would lead to the synthesis of SSA, which may serve as precursor for GABA or may be the substrate for SSADH.…”

Section: The Endogenous Ghb System In Brainmentioning

confidence: 99%

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

Maître

Klein

Mensah‐Nyagan

2016

Medicinal Research Reviews

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γ-Hydroxybutyrate (GHB) is both a natural brain compound with neuromodulatory properties at central GABAergic synapses (micromolar concentration range) and also a drug (Xyrem(R) ) clinically used for the treatment of various neurological symptoms (millimolar dose range). However, this drug has abuse potential and can be addictive for some patients. Here, we review the basic mechanistic role of endogenous GHB in brain as well as the properties and mechanisms of action for therapeutic clinical doses of exogenous GHB. Several hypotheses are discussed with a preference for a molecular mechanism that conciliates most of the findings available. This conciliatory model may help for the design of GHB-like drugs active at lower doses and devoid of major side effects.

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Section: The Endogenous Ghb System In Brainmentioning

confidence: 99%

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

Maître

Klein

Mensah‐Nyagan

2016

Medicinal Research Reviews

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“…It is a hepatoblastoma cell line derived from a 15-year-old male of European ancestry (4,5). Representing the human endodermal lineage, HepG2 cells are widely used as models for human toxicology studies (6–10), including toxicogenomic screens using CRISPR-Cas9 (11), in addition to studies on drug metabolism (12), cancer (13), liver disease (14), gene regulatory mechanisms (15) and biomarker discovery (16). As one of the main cell lines of the ENCyclopedia Of DNA Elements Project (ENCODE), HepG2 has been used to generate close to 1000 datasets for ENCODE (17).…”

Section: Introductionmentioning

confidence: 99%

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

et al. 2019

Nucleic Acids Research

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HepG2 is one of the most widely used human cancer cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher order genomic structural features are largely unknown. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data from HepG2 requires an understanding of the cell line’s genome sequence and genome structure. Using a variety of sequencing and analysis methods, we identified a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments at high resolution, SNVs and Indels (corrected for aneuploidy), regions with loss of heterozygosity, phased haplotypes extending to entire chromosome arms, retrotransposon insertions and structural variants (SVs) including complex and somatic genomic rearrangements. A large number of SVs were phased, sequence assembled and experimentally validated. We re-analyzed published HepG2 datasets for allele-specific expression and DNA methylation and assembled an allele-specific CRISPR/Cas9 targeting map. We demonstrate how deeper insights into genomic regulatory complexity are gained by adopting a genome-integrated framework.

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“…Expression of these enzymes has been demonstrated in the brain, liver, and kidney (50–52). Enzyme kinetic estimates for AKR1A1-mediated GHB metabolism have been evaluated in hepatocytes and suggest that AKR1A1 has a low affinity and high capacity for GHB metabolism (53). Partitioning into metabolic tissues must be corrected for the intrinsic clearance of a drug within the tissue.…”

Section: Discussionmentioning

confidence: 99%

The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific Nonlinear Distribution

Felmlee

Morse

Follman

et al. 2017

AAPS J

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The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. L-lactate administration decreased K values in liver, striatum, and hippocampus and increased K values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport.

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Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Cited by 12 publications

References 45 publications

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific Nonlinear Distribution

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