CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels

Josephson, Filip; Bertilsson, Leif; Böttiger, Ylva; Flamholc, Leo; Gisslén, Magnus; Ormaasen, Vidar; Sönnerborg, Anders; Diczfalusy, Ulf

doi:10.1007/s00228-008-0492-8

Cited by 55 publications

(74 citation statements)

References 12 publications

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“…However, the use of 4b-OHC as a biomarker for decreased CYP3A4 activity by enzyme inhibition with drugs may be limited due to the long half-life of this oxysterol, requiring weeks of inhibitor administration dmd.aspetjournals.org for reductions in plasma levels to become apparent (Josephson et al, 2008). In the context of disease effects on CYP3A4 activity, our results in NAFLD, as well as those reported for Crohn's disease (Iwamoto et al, 2013), show that 4b-OHC may be a valid biomarker of reduced metabolic activity for chronic conditions.…”

Section: Discussionmentioning

confidence: 99%

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Woolsey¹,

Mansell²,

Kim³

et al. 2015

Drug Metab Dispos

112

113

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Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4b-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4b-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4b-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipidloaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.

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Section: Discussionmentioning

confidence: 99%

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

Woolsey¹,

Mansell²,

Kim³

et al. 2015

Drug Metab Dispos

112

113

View full text Add to dashboard Cite

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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: 93%

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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“…8 Its plasma concentration increases in subjects treated with known CYP3A4 inducers such as carbamazepine, phenytoin, phenobarbital, rifampicin, ursodeoxycholic acid and efavirenz. 8,[30][31][32][33][34][35] It was also shown that inhibitors of CYP3A4, ritonavir and itraconazol, reduce the plasma level of 4b-hydroxycholesterol. 35,36 However, recently, TomalikScharte et al 37 reported a weak correlation between cholesterol-and midazolam-based CYP3A metrics and hence questioned the validity of 4b-hydroxycholesterol as a CYP3A biomarker.…”

Section: Cyp3a Markermentioning

confidence: 99%

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

et al. 2010

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The objectives of the this study were to assess the influence of CYP3A5 genotype and sex on the variability in total CYP3A activity and to compare 4b-hydroxycholesterol and omeprazole sulfoxidation as phenotypic markers for CYP3A activity in Ethiopians. Healthy subjects (n ¼ 150) were genotyped for CYP3A5*3, *6 and *7 using allele-specific PCR and Taqman genotyping assays. Plasma levels of 4b-hydroxycholesterol, 3 h post-dose omeprazole and omeprazole sulfone, were determined by gas chromatography-mass spectrometry and high performance liquid chromatography, respectively. The frequency of CYP3A5*1, *3, *6 and *7 was 20.5, 67.3, 12.2 and 0%, respectively. The mean plasma 4b-hydroxycholesterol level was 35.4 ng ml À1. The mean 4b-hydroxycholesterol level (P ¼ 0.0001) and the 4b-hydroxycholesterol/cholesterol ratio (P ¼ 0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4b-hydroxycholesterol concentration (P ¼ 0.003) and 4b-hydroxycholesterol/ cholesterol ratio (P ¼ 0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4b-hydroxycholesterol and 4b-hydroxycholesterol/cholesterol ratio in CYP3A5*0/*0 genotypes but not in individuals carrying the CYP3A5*1 allele. No correlation of omeprazole/omeprazole sulfone ratio with sex or CYP3A5 genotype was observed. A clear gene-dose effect implies plasma 4b-hydroxycholesterol level as a useful endogenous biomarker for total CYP3A activity (CYP3A5 plus CYP3A4) whereas the omeprazole/omeprazole sulfone ratio reflects mainly CYP3A4 activity. Sex and CYP3A5 genotype influence total CYP3A activity. Ethiopians display high total CYP3A activity and a unique distribution of CYP3A5 variant alleles not described hitherto.

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CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels

Cited by 55 publications

References 12 publications

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

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

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

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