Aldehyde Oxidase 1 (AOX1) in Human Liver Cytosols: Quantitative Characterization of AOX1 Expression Level and Activity Relationship
| العنوان: | Aldehyde Oxidase 1 (AOX1) in Human Liver Cytosols: Quantitative Characterization of AOX1 Expression Level and Activity Relationship |
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| المؤلفون: | Li Di, R. Scott Obach, Cexiong Fu, Catherine Soderstrom, Hui Zhang, Xiaogang Han, Mark Snyder, Matthew D. Troutman |
| المصدر: | Drug Metabolism and Disposition. 41:1797-1804 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Adult, Male, Pharmaceutical Science, Fractionation, Peptide Mapping, Cofactor, Young Adult, Cytosol, Tandem Mass Spectrometry, Humans, Aged, Pharmacology, chemistry.chemical_classification, biology, Chemistry, Metabolism, Middle Aged, Enzyme assay, Aldehyde Oxidase, Enzyme, Liver, Biochemistry, Toxicity, biology.protein, Female, Aldehyde oxidase 1, Chromatography, Liquid |
| الوصف: | Aldehyde oxidase 1 (AOX1) is a cytosolic enzyme highly expressed in liver and plays a key role in metabolizing drugs containing aromatic azaheterocyclic substituents. Rapid metabolism catalyzed by AOX1 can cause a drug to exhibit high clearance, low exposure, and hence decreased efficacy or even increased toxicity (if AOX1 generated metabolites are toxic). There is a need to develop the correlation between AOX1 expression levels and AOX1-substrate clearance. A fast, sensitive, and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify AOX1 in human liver cytosol for the first time. This LC-MS/MS method includes a straightforward ultrafiltration fractionation step and gives great selectivity and wide dynamic range (5.2 pM to 20.7 nM). The AOX1 levels in human liver cytosols of 20 donors were quantified using this method to investigate individual differences in AOX1 expression. No significant individual or gender differences in AOX1 levels were observed, although male donors exhibited a broader distribution than female donors (0.74-2.30 pmol/mg versus 0.74-1.69 pmol/mg, respectively). The AOX1 protein levels measured by LC-MS/MS were consistent with those measured by an enzyme-linked immunosorbent assay. Several donors have a normal AOX1 protein level but low enzyme activity, which might be due to cofactor deficiency, single nucleotide polymorphism, or homodimer dissociation. Cytosols from donors with chronic alcohol consumption had low AOX1-catalyzed carbazeran oxidation activities ( |
| تدمد: | 1521-009X 0090-9556 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c924a33bcf0c49cff4d7228a4f045b0eTest https://doi.org/10.1124/dmd.113.053082Test |
| رقم الانضمام: | edsair.doi.dedup.....c924a33bcf0c49cff4d7228a4f045b0e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1521009X 00909556 |
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