OCTN2 gene polymorphisms affect the chemotherapeutic sensitivity of oxaliplatin in colorectal cancer / 中国临床药理学与治疗学

AIM: To explore the effect of OCTN2 gene polymorphism on the expression and function of OCTN2, as well as the sensitivity of SW480 cells to oxaliplatin. METHODS: Four mutations of OCTN2 (F17L, E317K, S467C and P478L) transfected cell lines were constructed. Real-time RT-PCR and Western blot were used to detect the levels of OCTN2 mRNA and protein. The content of oxaliplatin was detected by HPLC. MTS assay was used to detect cell viability. RESULTS: The expression level of all mutant OCTN2 mRNA and protein was not significantly different from that of wild-type OCTN2. Oxaliplatin uptake experiments showed that there was no significant difference in V

Effect of arecoline hydrobromide on mRNA expression of hepatic and renal transporters in vivo / 中草药

Objective: To explore the effect of arecoline hydrobromide (AH) on the expression of rat hepatic and renal transporters. Methods: The effect of AH on the mRNA expression of 13 hepatic and renal transporters was studied after orally giver AH (0.8, 4, and 20 mg/kg/d) to rats for 21 d. Results: The results from the real-time PCR indicated that, AH treatment at low dose significantly decreased the mRNA levels of hepatic MRP2 and MDR1A, while significantly increased renal MRP5 mRNA level. On the other hand, AH treatment at high dose significantly inhibited the mRNA expression of hepatic OCT2, OAT2, OCTN2, OATP1A1, OATP1A4, OATP2B1, MRP2, and MDR1A, as well as renal MRP2, BCRP, and MDR1A. However, the mRNA expression of renal OCTN2, OATP1A1, OATP1A4, and MRP5 were significantly up-regulated following the treatment of high dose of AH. And the AH-induced effect on the above transporters was dose dependent in some extent. Conclusion: Due to the drug interaction caused by the alteration in expression and function of hepatic and renal transporters, it is suggested that the betel nut addicts should be paid more attention in case of adverse drug interactions.

Role of carnitine transporter in skeletal muscle energy metabolism / 体力科学

In skeletal muscle, carnitine is essential for the translocation of long-chain fatty-acids into the mitochondrial matrix for subsequent β-oxidation, and in the regulation of the mitochondrial acetyl coenzyme A/ free coenzyme A ratio by buffering excess acetyl groups. Based on the concept that increased carnitine availability is beneficial to skeletal muscle metabolic process, a large amount of research was directed towards investigating the effects of carnitine supplementation on exercise performance. However, it has been debated about contribution of carnitine for energy metabolism in skeletal muscle and whether carnitine supplementation can improve physical performance in healthy subjects. Recently, in order to resolve the issues, attention has been focused on the carnitine transport mechanism across the skeletal muscle plasma membrane. Due to lack of endogenous synthesis of carnitine in myocytes, skeletal muscles need to import this molecule from blood, suggesting that muscle carnitine uptake is most likely the limiting factor to muscle carnitine availability. It has been established that the specific carnitine transporter, OCTN2, is expressed in skeletal muscles and is assumed to transport carnitine into myocytes. Carnitine uptake capacity via the OCTN2, therefore, has been assumed to be one of the important factors to the skeletal muscle energy metabolism. The purpose of the review is to summarize the role of carnitine in skeletal muscle metabolism, and the current knowledge regarding the effect of carnitine supplementation of exercise performance. Furthermore, we summarize recent observations related to the carnitine transport mechanism in skeletal muscles including contribution of OCTN2 during muscle contraction.

Implementación de un método mediante el uso de sustratos tritiados comoherramienta diagnóstica de la deficiencia de OCTN2 / Implementation of a method using tritiated substrates as a diagnostic tool for OCTN2 deficiency

Introducción: El transporte de carnitina dentro de la célula es mediado por el transportador mitocondrial de los ácidos grasos de cadena larga. La deficiencia primaria de carnitina se debe a una deficiencia del transportador OCTN2. Objetivos: El presente estudio tuvo como objetivo el análisis de las tasas de oxidación de sustratos tritiados por fibroblastos de pacientes que presentaban deficiencia primaria de carnitina y controles. Materiales y métodos: Fibroblastos de pacientes y controles se incubaron con [3H]-palmitato y [3H]-miristato y se determinó la oxidación de los mismos en nmol/h/mg proteína. Resultados: Encontrßndose deficiente la oxidación de sustratos tritiados en mßs de 60% por parte de los fibroblastos procedentes de los pacientes que presentaban la deficiencia de OCTN2. Conclusión: Esta técnica modificada permite el diagnóstico in vitro de la deficiencia primaria de carnitina.

Introduction: The transport of carnitine into the cell is mediated by a high-affinity sodium-dependent plasmalemmal carnitine transporter, OCTN2. Carnitine is a zwitterion essential for the mitochondrial oxidation of long-chain fatty acids. Primary carnitine deficiency is a consequence of the deficiency of OCTN2. Objective: The objective of the present study was to analyse the oxidation rate of tritiated substrates by fibroblasts from patients suffering OCTN2 deficiency and controls. Materials and methods: Fibroblasts from patients and controls were incubated with [3H]-palmitate and [3H]-miristate and the oxidation of these substrates were measured in nmol/hour/mg protein. Results: We found depressed the oxidation of tritiated substrates in fibroblasts from patients suffering the deficiency of OCTN2 in more than 60%.Conclusion: This modified technique enables us the in vitro diagnosis or primary carnitine deficiency.