Quantification of 4-Beta-Hydroxycholesterol in Human Plasma Using Automated Sample Preparation and LC-ESI-MS/MS Analysis

Goodenough, Angela K.; Onorato, Joelle M.; Ouyang, Zheng; Chang, Sang‐Yoon; Rodrigues, A. David; Kasichayanula, Sreeneeranj; Huang, Shu-Pang; Turley, Wesley A.; Burrell, Richard C.; Bifano, Marc; Jemal, Mohammed; LaCreta, Frank; Tymiak, Adrienne A.; Wang‐Iverson, David

doi:10.1021/tx2001898

Cited by 45 publications

(45 citation statements)

References 43 publications

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“…To the best of our knowledge, plasma concentration of 4 ␤ -hydroxycholesterol in patients with renal failure has not been reported previously, which makes comparison impossible. However, our levels are within the range of 18.8-77.0 ng/ml reported by other groups in healthy volunteers ( 18,21,23,25,34,35 ).…”

Section: Discussionsupporting

confidence: 67%

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Suzuki

Sato

Kawasaki

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Phenotyping of cytochrome CYP3A seems to be of special importance because enzymes belonging to this family, particularly CYP3A4, are involved in the metabolism of more than 50% of currently prescribed drugs. However, the selection of an appropriate CYP3A phenotyping substrate and metric is still a matter of discussion, although some CYP3A test substrates, including midazolam, erythromycin, alprazolam, and nifedipine have been proposed ( 15 ). However, administration of these drugs poses challenges in specifi c patient populations such as pediatric and elderly patients, transplant recipients, and cancer patients, in whom administration of probe drugs may have a negative impact on patient safety. Identifi cation of an appropriate endogenous CYP3A substrate and corresponding metrics would be a promising alternative, allowing simple and possibly broader application of the phenotyping approach. Oxidation of the endogenous compound cortisol to 6 ␤ -hydroxycortisol has been shown to be a CYP3A-dependent pathway in humans. Consequently, a urinary 6 ␤ -hydroxycortisol-to-cortisol ratio has been proposed as a suitable phenotyping marker for the assessment of CYP3A activity ( 16,17 ). However, the sensitivity of the method to detect small changes in enzyme activity is low because of pronounced background variation ( 17 ). Another compound, 4 ␤ -hydroxycholesterol, which is identifi ed as one of the major oxysterols in humans, was reported to be formed solely by CYP3A4 ( 18 ). Markedly elevated concentrations of 4 ␤ -hydroxycholesterol were found in patients treated with CYP3A4 inducers ( 19-23 ), and decreased concentrations in patients treated with CYP3A4 inhibitors ( 22-24 ). Furthermore, a relationship between blood 4 ␤ -hydroxycholesterol concentration and the number of active CYP3A5*1 alleles has been demonstrated, suggesting that 4 ␤ -hydroxycholesterol is formed not only by CYP3A4 but also by CYP3A5 ( 25 ). Accordingly, 4 ␤ -hydro xycholesterol has been proposed to be a potential endogenous biomarker of CYP3A activity. Impaired renal function alters the clearance of many drugs mainly by decreasing their renal elimination. However, several studies in rats ( 1-6 ) and in patients ( 7-9 ) have shown that renal failure also decreases the metabolic clearance of drugs, particularly those metabolized by cytochrome P450 (CYP). The underlying causes of altered CYP functional expression observed in kidney disease remain unclear, but several studies indicate that uremic toxins ( 10-13 ) and infl ammation ( 14 ) may play a role via transcriptional or translational modifi cations of CYP enzymes.

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Section: Discussionsupporting

confidence: 67%

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Suzuki

Sato

Kawasaki

et al. 2013

Journal of Lipid Research

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“…DHEA, dehydroepiandrosterone. 4b-hydroxycholesterol and occasionally the 4b-hydroxycholesterol/ cholesterol ratio have been studied after rifampin induction (Goodenough et al, 2011;Björkhem et al, 2013;Shin et al, 2013) and with inhibitors such as ketoconazole (Goodenough et al, 2011;Shin et al, 2013). Overall, rigorous validation of 4b-hydroxycholesterol as a CYP3A marker has been yet to be performed.…”

Section: Interindividual Variability In Cyp2d6-mediated Drugmentioning

confidence: 99%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

151

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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“…Among them, 4b-hydroxycholesterol was first reported to be formed solely by CYP3A4 (Bodin et al, 2001). Markedly elevated concentrations of 4b-hydroxycholesterol were found in patients treated with CYP3A4 inducers (Niemi et al, 2006;Josephson et al, 2008;Wide et al, 2008;Diczfalusy et al, 2009;Goodenough et al, 2011), and decreased concentrations have been detected in patients treated with CYP3A4 inhibitors (Josephson et al, 2008;Lütjohann et al, 2009;Goodenough et al, 2011). Furthermore, a relationship between blood 4b-hydroxycholesterol concentration and the number of active CYP3A5*1 alleles has been demonstrated, suggesting that 4b-hydroxycholesterol is not only formed by CYP3A4, but also by CYP3A5 .…”

Section: Introductionmentioning

confidence: 99%

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

et al. 2013

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Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4b-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4b-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4b-hydroxycholesterol were 57.1 6 11.2, 42.1 6 11.8, and 34.5 6 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4b-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4b-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure.

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Quantification of 4-Beta-Hydroxycholesterol in Human Plasma Using Automated Sample Preparation and LC-ESI-MS/MS Analysis

Cited by 45 publications

References 43 publications

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

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