13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Role of Perivascular Adipose Tissue in Health and Disease.

Compr Physiol. 2017 Dec 12;8(1):23-59

Authors: Fernández-Alfonso MS, Somoza B, Tsvetkov D, Kuczmanski A, Dashwood M, Gil-Ortega M

Abstract
Perivascular adipose tissue (PVAT) is cushion of fat tissue surrounding blood vessels, which is phenotypically different from other adipose tissue depots. PVAT is composed of adipocytes and stromal vascular fraction, constituted by different populations of immune cells, endothelial cells, and adipose-derived stromal cells. It expresses and releases an important number of vasoactive factors with paracrine effects on vascular structure and function. In healthy individuals, these factors elicit a net anticontractile and anti-inflammatory paracrine effect aimed at meeting hemodynamic and metabolic demands of specific organs and regions of the body. Pathophysiological situations, such as obesity, diabetes or hypertension, induce changes in its amount and in the expression pattern of vasoactive factors leading to a PVAT dysfunction in which the beneficial paracrine influence of PVAT is shifted to a pro-oxidant, proinflammatory, contractile, and trophic environment leading to functional and structural cardiovascular alterations and cardiovascular disease. Many different PVATs surrounding a variety of blood vessels have been described and exhibit regional differences. Both protective and deleterious influence of PVAT differs regionally depending on the specific vascular bed contributing to variations in the susceptibility of arteries and veins to vascular disease. PVAT therefore, might represent a novel target for pharmacological intervention in cardiovascular disease. © 2018 American Physiological Society. Compr Physiol 8:23-59, 2018.

PMID: 29357124 [PubMed - in process]

Vitamin D pathway gene polymorphisms and hepatocellular carcinoma in chronic hepatitis C-affected patients treated with new drugs.

Cancer Chemother Pharmacol. 2018 Jan 22;:

Authors: Cusato J, Boglione L, De Nicolò A, Favata F, Ariaudo A, Mornese Pinna S, Guido F, Avataneo V, Cantù M, Carcieri C, Cariti G, Di Perri G, D'Avolio A

Abstract
PURPOSE: Since HCV infection may lead to hepatocellular carcinoma (HCC) and vitamin D (deficiency) is related to cancer, we investigated if SNPs in genes involved in vitamin D pathway could predict HCV-related HCC presence in patients treated with new anti-HCV drugs.
METHODS: Patients with chronic hepatitis C and treated with direct-acting antivirals were enrolled. SNPs in VDR, CYP27B1, CYP24A1 and GC genes were assessed through real-time PCR. 258 patients were analyzed.
RESULTS: HCC was present in six patients, all taking sofosbuvir, all males and five/six had cirrhosis. HCV-RNA log levels at baseline were statistically different between patients with and without HCC. VDR FokI T > C SNP resulted associated with HCC: all the CC patients were free from HCC. An association between HCC presence and undetectable HCV-RNA at 1 month of therapy was suggested; cirrhosis was related to HCC. HCC risk factors were age, ribavirin administration, IL28Brs12979860CC and previous treatments; VDR FokICC, sex and insulin resistance were protective factors.
CONCLUSIONS: These data highlighted vitamin D pathway gene SNPs and HCC relationship in the Italian population; further studies are required.

PMID: 29356898 [PubMed - as supplied by publisher]

Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development.

OMICS. 2018 Jan;22(1):17-34

Authors: Dzobo K, Senthebane DA, Thomford NE, Rowe A, Dandara C, Parker MI

Abstract
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.

PMID: 29356626 [PubMed - in process]

From Genomics to Omics Landscapes of Parkinson's Disease: Revealing the Molecular Mechanisms.

OMICS. 2018 Jan;22(1):1-16

Authors: Redenšek S, Dolžan V, Kunej T

Abstract
Molecular mechanisms of Parkinson's disease (PD) have already been investigated in various different omics landscapes. We reviewed the literature about different omics approaches between November 2005 and November 2017 to depict the main pathological pathways for PD development. In total, 107 articles exploring different layers of omics data associated with PD were retrieved. The studies were grouped into 13 omics layers: genomics-DNA level, transcriptomics, epigenomics, proteomics, ncRNomics, interactomics, metabolomics, glycomics, lipidomics, phenomics, environmental omics, pharmacogenomics, and integromics. We discussed characteristics of studies from different landscapes, such as main findings, number of participants, sample type, methodology, and outcome. We also performed curation and preliminary synthesis of multiple omics data, and identified overlapping results, which could lead toward selection of biomarkers for further validation of PD risk loci. Biomarkers could support the development of targeted prognostic/diagnostic panels as a tool for early diagnosis and prediction of progression rate and prognosis. This review presents an example of a comprehensive approach to revealing the underlying processes and risk factors of a complex disease. It urges scientists to structure the already known data and integrate it into a meaningful context.

PMID: 29356624 [PubMed - in process]

Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis.

Mol Neurobiol. 2016 Oct;53(8):5457-67

Authors: Haerian BS, Baum L, Kwan P, Cherny SS, Shin JG, Kim SE, Han BG, Tan HJ, Raymond AA, Tan CT, Mohamed Z

Abstract
Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case-control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case-control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10(-5), and TT vs. CC, p = 2 × 10(-5)) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10(-6)). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10(-4), and p = 4 × 10(-3), respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.

PMID: 26452361 [PubMed - indexed for MEDLINE]

Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease.

Neurobiol Aging. 2017 Dec 20;64:92-106

Authors: Cramer PE, Gentzel RC, Tanis KQ, Vardigan J, Wang Y, Connolly B, Manfre P, Lodge K, Renger JJ, Zerbinatti C, Uslaner JM

Abstract
While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.

PMID: 29353102 [PubMed - as supplied by publisher]

Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: The Role of Cancer Stem Cells.

Stem Cells. 2018 Jan 20;:

Authors: Del Re M, Arrigoni E, Restante G, Passaro A, Rofi E, Crucitta S, De Marinis F, Di Paolo A, Danesi R

Abstract
Among the potential mechanisms involved in resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), the manifestation of stem-like properties in cancer cells seems to have a crucial role. Alterations involved in the development of TKI resistance may be acquired in a very early phase of tumorigenesis, supporting the hypothesis that these aberrations may be present in cancer stem cells (CSCs). In this regard, the characterization of tumor subclones in the initial phase and the identification of the CSCs may be helpful in planning a specific treatment to target selected biomarkers, suppress tumor growth, and prevent drug resistance. The aim of this review is to elucidate the role of CSCs in the development of resistance to TKIs and its implication for the management of patients. This article is protected by copyright. All rights reserved.

PMID: 29352734 [PubMed - as supplied by publisher]

Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing.

Pharmacogenomics J. 2018 Jan 19;:

Authors: Mimori T, Yasuda J, Kuroki Y, Shibata TF, Katsuoka F, Saito S, Nariai N, Ono A, Nakai-Inagaki N, Misawa K, Tateno K, Kawai Y, Fuse N, Hozawa A, Kuriyama S, Sugawara J, Minegishi N, Suzuki K, Kinoshita K, Nagasaki M, Yamamoto M

Abstract
Human leukocyte antigen (HLA) is a gene complex known for its exceptional diversity across populations, importance in organ and blood stem cell transplantation, and associations of specific alleles with various diseases. We constructed a Japanese reference panel of class I HLA genes (ToMMo HLA panel), comprising a distinct set of HLA-A, HLA-B, HLA-C, and HLA-H alleles, by single-molecule, real-time (SMRT) sequencing of 208 individuals included in the 1070 whole-genome Japanese reference panel (1KJPN). For high-quality allele reconstruction, we developed a novel pipeline, Primer-Separation Assembly and Refinement Pipeline (PSARP), in which the SMRT sequencing and additional short-read data were used. The panel consisted of 139 alleles, which were all extended from known IPD-IMGT/HLA sequences, contained 40 with novel variants, and captured more than 96.5% of allelic diversity in 1KJPN. These newly available sequences would be important resources for research and clinical applications including high-resolution HLA typing, genetic association studies, and analyzes of cis-regulatory elements.

PMID: 29352165 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

CYP3A Activity and Rivaroxaban Serum Concentrations in Russian Patients with Deep Vein Thrombosis.

Genet Test Mol Biomarkers. 2018 Jan;22(1):51-54

Authors: Sychev DA, Vardanyan A, Rozhkov A, Hachatryan E, Badanyan A, Smirnov V, Ananichuk A, Denisenko N

Abstract
BACKGROUND: Rivaroxaban is metabolized in the liver via CYP3A4, the cytochrome involved in the metabolism of nearly 50% of all medications. Thus, its effective concentration depends on multiple pharmacologic parameters.
METHODS: The primary goal of our research was to study the correlation between the CYP3A family activity and the safety and efficacy of anticoagulant therapy with rivaroxaban in patients with deep vein thrombosis (DVT). Thirty one patients with DVT aged 21-83 years, 18 men and 13 women, received rivaroxaban (Xarelto) 30 mg/day for 21 days after diagnosis and 20 mg/day for the follow-up period of 6 months. During the study period, Doppler ultrasound was performed weekly to assess the clot dynamics and recanalization time.
RESULTS: We found a direct statistically reliable correlation between CYP3A4 activity and both peak and trough rivaroxaban levels. A correlation was also found between the initial clot length and the time to full recanalization r = 0.764 (0.554-0.883), p < 0.0001. No significant link was found between either the glomerular filtration rate and peak rivaroxaban concentrations or between CYP3A4 activity and the treatment effectiveness parameters. No connection between renal function and rivaroxaban concentration was established in our study, which agrees with the clinical trials data that allow unlimited rivaroxaban use in patients with glomerular filtration rate >30 mL/min.
CONCLUSIONS: The direct link between the initial clot length and time to full recanalization that has been found means that patients with more advanced stages of thrombosis need more time to reach recanalization than their counterparts with a less severe condition.

PMID: 29345985 [PubMed - in process]

GLCCI1 polymorphism rs37973 and asthma treatment response to inhaled corticosteroids.

J Investig Allergol Clin Immunol. 2018 Jan 17;:0

Authors: Rijavec M, Žavbi M, Lopert A, Fležar M, Korošec P

Abstract
BACKGROUND: Asthma treatment response is highly variable and pharmacogenetic markers that predict treatment response would be one step closer to personalized treatment. GWAS studies have shown that polymorphisms GLCCI1 could be associated with asthma treatment response to inhaled corticosteroids (ICS).
MATERIAL AND METHODS: We genotyped rs37973 of GLCCI1 in 208 adult asthma patients treated with ICS. Change in % predicted FEV1 was analysed after short-term (3 months) and after long-term (at least 3 years) treatment. Treatment success was defined as good when FEV1 decreased less than 30 ml/year.
RESULTS: After 3 months of treatment, change of % predicted FEV1 was higher in patients with GG genotype than in patients with AG+AA genotype, and this genotype dependent difference was only evident in non-smokers. Similar results were found after at least 3 years of treatment when all patients were analysed, in non-smokers and patients with atopy. Even though, no differences in treatment success (good vs. poor response) were observed when analysing the entire group of patients, genotype dependent treatment success was highly influenced by smoking and atopy. GG genotype was overrepresented in non-smokers and patients with atopy with good response.
CONCLUSIONS: Rs37973 was associated with short- and long-term treatment response; however, there was a great influence of smoking and atopy on pharmacogenetic association. Furthermore, we found GG genotype to be associated with better treatment response, what is contrary to results found in GWAS.

PMID: 29345236 [PubMed - as supplied by publisher]

Selective serotonin reuptake inhibitor use in pregnant women; pharmacogenetics, drug-drug interactions and adverse effects.

Expert Opin Drug Metab Toxicol. 2018 Jan 18;:

Authors: Ornoy A, Koren G

Abstract
INTRODUCTION: Possible negative effects of selective serotonin reuptake inhibitors (SSRIs) in pregnancy relate to congenital anomalies, negative perinatal events and neurodevelopmental outcome. Many studies are confounded by the underlying maternal disease and by pharmacogenetic and pharmacokinetic differences of these drugs. Areas covered: The possible interactions of SSRIs and serotonin and norepinephrine reuptake inhibitors with other drugs and the known effects of SSRIs on congenital anomalies, perinatal and neurodevelopmental outcome. Expert opinion: SSRIs should be given with caution when combined with other drugs that are metabolized by cytochrome P450 enzymes. SSRIs apparently increase the rate of severe cardiac malformations, induce neonatal adaptation problems in up to 30% of the offspring, increase the rate of persisten pulmonary hypertension of the newborn and possibly slightly increase the rate of prematurity and low birth weight. Most neurodevelopmental follow up studies did not find significant cognitive impairments except some transient gross motor delay, slight impairment of language abilities and possibly behavioral changes. The literature on the possible association of SSRIs with autism spectrum disorder is inconsistent; if an association exists, it is apparently throughout pregnancy. The risk associated with treatment discontinuation seems to outweigh the risk of treatment, as severe maternal depression may negatively affect the child's development. If needed, treatment should continue in pregnancy with the minimal effective dose.

PMID: 29345153 [PubMed - as supplied by publisher]

Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-sulfate, A Major Circulating Vitamin D Metabolite in Humans.

Drug Metab Dispos. 2018 Jan 17;:

Authors: Wong T, Wang Z, Chapron BD, Suzuki M, Claw KG, Gao C, Foti RS, Prasad B, Chapron A, Calamia J, Chaudhry A, Schuetz EG, Horst RL, Mao Q, de Boer IH, Thornton TA, Thummel KE

Abstract
Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in regulating the biological effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD3 has been extensively investigated, limited information is available on the conjugation of 25OHD3. In the present study, we report that 25OHD3 is selectively conjugated to 25OHD3-3-O-sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD3, 25OHD3-3-O-sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route. In addition, 25OHD3 sulfonation was not inducible by the potent hPXR agonist, rifampicin. The 25OHD3 sulfonation rates in a bank of 258 different human liver cytosols were highly variable, but correlated with the rates of dehydroepiandrosterone sulfonation. Further analysis revealed a significant association between a common SNV within intron-1 of SULT2A1 (rs296361; MAF = 15% in Whites) and liver cytosolic SULT2A1 content as well as 25OHD3-3-O-sulfate formation rate, suggesting that variation in the SULT2A1 gene contributes importantly to inter-individual differences in vitamin D homeostasis. Finally, 25OHD3-3-O-sulfate exhibited high affinity for the vitamin D binding protein and was detectable in human plasma and bile, but not in urine samples. Thus, circulating concentrations of 25OHD3-3-O-sulfate appear to be protected from rapid renal elimination, raising the possibility that the sulfate metabolite may serve as a reservoir of 25OHD3 in vivo, and contribute indirectly to the biological effects of vitamin D.

PMID: 29343609 [PubMed - as supplied by publisher]

Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck?

Ann Oncol. 2017 01 01;28(1):183

Authors: Danesi R, Del Re M, Ciccolini J, Schellens JHM, Schwab M, van Schaik RHN, van Kuilenburg ABP

PMID: 27687313 [PubMed - indexed for MEDLINE]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/01/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Prescription medication changes following direct-to-consumer personal genomic testing: findings from the Impact of Personal Genomics (PGen) Study.

Genet Med. 2017 May;19(5):537-545

Authors: Carere DA, VanderWeele TJ, Vassy JL, van der Wouden CH, Roberts JS, Kraft P, Green RC

Abstract
PURPOSE: To measure the frequency of prescription medication changes following direct-to-consumer personal genomic testing (DTC-PGT) and their association with the pharmacogenomic results received.
METHODS: New DTC-PGT customers were enrolled in 2012 and completed surveys prior to the return of results and 6 months after results; DTC-PGT results were linked to survey data. "Atypical response" pharmacogenomic results were defined as those indicating an increase or decrease in risk of an adverse drug event or likelihood of therapeutic benefit. At follow-up, participants reported prescription medication changes and health-care provider consultation.
RESULTS: Follow-up data were available from 961 participants, of whom 54 (5.6%) reported changing a medication they were taking or starting a new medication due to their DTC-PGT results. Of these, 45 (83.3%) reported consulting with a health-care provider regarding the change. Pharmacogenomic results were available for 961 participants, of which 875 (91.2%) received one or more atypical response results. For each such result received, the odds of reporting a prescription medication change increased 1.57 times (95% confidence interval = 1.17, 2.11).
CONCLUSION: Receipt of pharmacogenomic results indicating an atypical drug response is common with DTC-PGT and is associated with prescription medication changes; however, fewer than 1% of consumers report unsupervised changes at 6 months after testing.Genet Med advance online publication 22 September 2016.

PMID: 27657683 [PubMed - in process]

Payer decision making for next-generation sequencing-based genetic tests: insights from cell-free DNA prenatal screening.

Genet Med. 2017 May;19(5):559-567

Authors: Dervan AP, Deverka PA, Trosman JR, Weldon CB, Douglas MP, Phillips KA

Abstract
PURPOSE: Cell-free DNA (cfDNA) prenatal screening tests have been rapidly adopted into clinical practice, due in part to positive insurance coverage. We evaluated the framework payers used in making coverage decisions to describe a process that should be informative for other sequencing tests.
METHODS: We analyzed coverage policies from the 19 largest US private payers with publicly available policies through February 2016, building from the University of California San Francisco TRANSPERS Payer Coverage Policy Registry.
RESULTS: All payers studied cover cfDNA screening for detection of trisomies 21, 18, and 13 in high-risk, singleton pregnancies, based on robust clinical validity (CV) studies and modeled evidence of clinical utility (CU). Payers typically evaluated the evidence for each chromosomal abnormality separately, although results are offered as part of a panel. Starting in August 2015, 8 of the 19 payers also began covering cfDNA screening in average-risk pregnancies, citing recent CV studies and updated professional guidelines. Most payers attempted, but were unable, to independently assess analytic validity (AV).
CONCLUSION: Payers utilized the standard evidentiary framework (AV/CV/CU) when evaluating cfDNA screening but varied in their interpretation of the sufficiency of the evidence. Professional guidelines, large CV studies, and decision analytic models regarding health outcomes appeared highly influential in coverage decisions.Genet Med advance online publication 22 September 2016.

PMID: 27657682 [PubMed - in process]

CYP3A Specifically Catalyzes 1β-Hydroxylation of Deoxycholic Acid: Characterization and Enzymatic Synthesis of a Potential Novel Urinary Biomarker for CYP3A Activity.

Drug Metab Dispos. 2016 Sep;44(9):1480-9

Authors: Hayes MA, Li XQ, Grönberg G, Diczfalusy U, Andersson TB

Abstract
The endogenous bile acid metabolite 1β-hydroxy-deoxycholic acid (1β-OH-DCA) excreted in human urine may be used as a sensitive CYP3A biomarker in drug development reflecting in vivo CYP3A activity. An efficient and stereospecific enzymatic synthesis of 1β-OH-DCA was developed using a Bacillus megaterium (BM3) cytochrome P450 (P450) mutant, and its structure was confirmed by nuclear magnetic resonance (NMR) spectroscopy. A [(2)H4]-labeled analog of 1β-OH-DCA was also prepared. The major hydroxylated metabolite of deoxycholic acid (DCA) in human liver microsomal incubations was identified as 1β-OH-DCA by comparison with the synthesized reference analyzed by UPLC-HRMS. Its formation was strongly inhibited by CYP3A inhibitor ketoconazole. Screening of 21 recombinant human cytochrome P450 (P450) enzymes showed that, with the exception of extrahepatic CYP46A1, the most abundant liver P450 subfamily CYP3A, including CYP3A4, 3A5, and 3A7, specifically catalyzed 1β-OH-DCA formation. This indicated that 1β-hydroxylation of DCA may be a useful marker reaction for CYP3A activity in vitro. The metabolic pathways of DCA and 1β-OH-DCA in human hepatocytes were predominantly via glycine and, to a lesser extent, via taurine and sulfate conjugation. The potential utility of 1β-hydroxylation of DCA as a urinary CYP3A biomarker was illustrated by comparing the ratio of 1β-OH-DCA:DCA in a pooled spot urine sample from six healthy control subjects to a sample from one patient treated with carbamazepine, a potent CYP3A inducer; 1β-OH-DCA:DCA was considerably higher in the patient versus controls (ratio 2.8 vs. 0.4). Our results highlight the potential of 1β-OH-DCA as a urinary biomarker in clinical CYP3A DDI studies.

PMID: 27402728 [PubMed - in process]