Conséquences toxicogénomiques de la surexpression du CYP2C9 dans les cellules HepG2

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Idiosyncratiques et « omiques » peuvent-ils rimer ?

Les toxicités idiosyncratiques sont des effets indésirables rares induits par des médicaments. Ces réactions ne sont généralement pas prédites pendant la phase de développement des médicaments, mais peuvent conduire au décès des patients. L’utilisation d’outils puissants comme les technologies « omiques » (génomiques, transcriptomiques, protéomiques, métabonomiques, etc.) permet-elle de prédire ces réactions ? Nous présentons dans cette revue des études génomiques qui ont permis d’identifier de nouveaux biomarqueurs utilisés pour prévenir les effets indésirables chez les patients et des études transcriptomiques. Celles-ci ont mis en évidence des processus biologiques altérés par l’exposition au médicament et ont ainsi amélioré la compréhension mécanistique des toxicités

APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair.: Kidney donation in twins with APOL1 variant

International audienceWe report an occurrence of progressive loss of transplant function and ultimately transplant failure after living related kidney transplantation involving monozygotic twin brothers of Afro-Caribbean origin who were both heterozygous for the G1 and G2 kidney disease risk alleles in the APOL1 gene, which encodes apolipoprotein L-I. A 21-year-old man with end-stage kidney disease of unknown cause received a kidney from his brother, who was confirmed as a monozygotic twin by microsatellite analysis. Thirty months after transplantation, the patient presented with proteinuria and decreased estimated glomerular filtration rate; a biopsy of the transplant showed typical focal segmental glomerulosclerosis lesions. He received steroid therapy, but progressed to kidney failure 5 years later. The twin brother had normal kidney function without proteinuria at the time of transplantation; however, 7 years later, he was found to have decreased estimated glomerular filtration rate (40mL/min/1.73m(2)) and proteinuria (protein excretion of 2.5g/d). APOL1 genotyping revealed that both donor and recipient were heterozygous for the G1 and G2 alleles. This case is in stark contrast to the expected course of kidney transplantation in identical twins and suggests a role for APOL1 polymorphisms in both the donor and recipient

A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency

International audienceAbstract Background Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD-deficient patients remains elusive. Methods Among a nationwide cohort of 5886 phenotyped patients with cancer who were screened for DPD deficiency over a 3 years period, we assessed the characteristics of both DPD phenotypes and DPYD genotypes in a subgroup of 3680 patients who had completed the two tests. The extent to which defective allelic variants of DPYD predict DPD activity as estimated by the plasma concentrations of uracil [U] and its product dihydrouracil [UH 2 ] was evaluated. Results When [U] was used to monitor DPD activity, 6.8% of the patients were classified as having DPD deficiency ([U] > 16 ng/ml), while the [UH 2 ]:[U] ratio identified 11.5% of the patients as having DPD deficiency (UH 2 ]:[U]  150 ng/ml), and [UH 2 ]:[U] < 1 identified three patients (0.08%) with a complete DPD deficiency. A defective DPYD variant was present in 4.5% of the patients, and two patients (0.05%) carrying 2 defective variants of DPYD were predicted to have low metabolism. The mutation status of DPYD displayed a very low positive predictive value in identifying individuals with DPD deficiency, although a higher predictive value was observed when [UH 2 ]:[U] was used to measure DPD activity. Whole exon sequencing of the DPYD gene in 111 patients with DPD deficiency and a “wild-type” genotype (based on the four most common variants) identified seven heterozygous carriers of a defective allelic variant. Conclusions Frequent genetic DPYD variants have low performances in predicting partial DPD deficiency when evaluated by [U] alone, and [UH 2 ]:[U] might better reflect the impact of genetic variants on DPD activity. A clinical trial comparing toxicity rates after dose adjustment according to the results of genotyping or phenotyping testing to detect DPD deficiency will provide critical information on the best strategy to identify DPD deficiency

Current diagnostic and clinical issues of screening for dihydropyrimidine dehydrogenase deficiency

International audienc

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance

<div><p>We have investigated <i>in vitro</i> the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined.</p><p>Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation.</p><p>CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.</p></div

Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers

International audienceP-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by similar to 38% (p &lt; 0.0001), 13% (p &lt; 0.0001), and 13% (p &lt; 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by similar to 24% (p &lt; 0.001), 10% (p &lt; 0.001), and 23.6% (p &lt; 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters

Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.

BACKGROUND: Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. METHODS: Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. RESULTS: Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUC(cum)) was independently associated with any grade ≥ 3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥ 2 diarrhea (p = 0.015) and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUC(cum) value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018). CONCLUSION: In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results

Disappearance of TKI in in culture media.

<p>Disappearance of TKI (2.5 µM added in the culture media at T = 0) in culture media of HepG2 cell infected with lacZ (control), CYP1A1, 1B1, 2J2 and 3A4. Disappearance of TKI was determined by LC-MS analysis and is given in % of the levels at T = 0. A) Remaining TKI in the culture media after 72 hours (representative experiment from 3 experiments in percent of initial TKI levels). Time course of B) dasatinib, C) nilotinib and D) sorafenib disappearance in the incubations are depicted for cytochrome P-450 (CYP) 1A1, 1B1 and 2J2 isozymes.</p

mRNA relative expression of CYP1A1, 1B1, 2J2 and 3A4.

<p>Mean +/− SD of the total mRNA relative expression of CYP1A1, 1B1, 2J2 and 3A4 in A) hepatocellular carcinoma (HCC; N = 6 and B) renal cell carcinoma (RCC; N = 14) and the healthy tissues counterpart surrounding the tumors. Correlation between total mRNA expression found in healthy tissues for C) CYP2J2 for HCC and for D) CYP1B1 for RCC and E) CYP2J2 for RCC. Outliers with very high mRNA expression can be observed and are highlighted with arrows.</p