Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients

Grabar, Petra Bohanec; Rozman, B; Tomšič, Matija; Šuput, Daša; Logar, D; Dolžan, Vita

doi:10.1007/s00228-008-0498-2

Cited by 78 publications

(42 citation statements)

References 22 publications

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“…The 16 However, no homozygotes for the CYP2C19*17 were found in our patient group. We have not analyzed other variant CYP2C19 alleles in our study.…”

Section: Resultscontrasting

confidence: 55%

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Grošelj¹,

Tanšek²,

Podkrajšek³

et al. 2016

ACSi

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Extraadrenal enzymes such as CYP2C19 may participate in residual 21-hydroxylation of progesterone leading to milder phenotypes of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Among 94 21OHD patients from the Slovene national registry 28 were homozygous or compound heterozygous for severe CYP21A2 mutations. We have reviewed their clinical phenotype and obtained information on maintenance doses of hydrocortisone and fludrocortisone. All patients were genotyped for CYP2C19*2 and CYP2C19*17 alleles. Among eleven patients with CYP2C19*1/*17 genotype, all had salt-wasting 21OHD. Out of 17 patients with CYP2C19 genotypes leading to normal or decreased CYP2C19 activity, 15 had salt-wasting, one had simple virilizing and one had non-classical 21OHD. CYP2C19*1/*17 genotype was associated with lower maintenance dose of fludrocortisone (p = 0.04), but not of hydrocortisone (p > 0.05). Increased CYP2C19 activity could slightly ameliorate mineralocorticoid deficiency in 21OHD.

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“…The 16 However, no homozygotes for the CYP2C19*17 were found in our patient group. We have not analyzed other variant CYP2C19 alleles in our study.…”

Section: Resultscontrasting

confidence: 55%

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Grošelj¹,

Tanšek²,

Podkrajšek³

et al. 2016

ACSi

Self Cite

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“…In fact, the mitochondrial membrane potential of primary rat hepatocytes did show more sensitive to LEF than Figure S1). Many reports demonstrated that the polymorphism of several CYPs, such as CYP1A2 and CYP2C19, could affect the liver toxicity of LEF in patients with rheumatoid arthritis [24][25][26] , which could be indirect evidences that CYPs play a critical role in the detoxification of LEF in the body. Our studies with HRN mice are the first direct in vivo evidences that hepatic CYPs are involved in the clearance and toxicity of LEF.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg • kg, ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC 50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC 0-t ) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg • kg -1 • d -1 ) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg • kg, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

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“…A recent study found significant differences in CYP1A2 activity between ethnic groups (Swedes and Koreans), not related to environmental factors. 37 CYP1A2 polymorphisms could also be related to the toxicity of leflunomide in patients with rheumatoid arthritis 38 and seem to have a role in the efficacy of treatment of patients with antipsychotics, such as clozapine and olanzepine. 39 Several studies indicated implications of CYP1A2 polymorphisms in cancer susceptibility, namely for pancreatic cancer 40 and bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of eight human cytochrome P450 1A2 gene variants by recombinant protein expression

et al. 2010

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Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients

Abstract: Our results suggest that the CYP1A2*1F allele may be associated with leflunomide toxicity in RA patients.

Cited by 78 publications

References 22 publications

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Functional characterization of eight human cytochrome P450 1A2 gene variants by recombinant protein expression

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