Association between the organic cation transporter 3 methylation and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and has a high death rate in the world. This research while examining the expression of OCT3 at the mRNA level has also studied gene methylation profile in patients with HCC in comparison with people without HCC. The volunteers were: patients with HCC (n=81) and a healthy control group (n=90). The expression of OCT3was studied using the qRT-PCR method. The methylation profile was evaluated by genomic DNA using methylation specific PCR (MSP) method. The expression level of OCT3 marker mRNA in patients has decreased significantly compared to healthy individuals (0.58 ± 0.311 vs 1.20 ± 0.355, P <0.001). No significant statistical relationship was found between demographic data and OCT3 expression in participants (P >0.05). The amount of methylation (UM + MM) in cancer patients has raised vs controls (P <0.001) and has increased the risk of cancer (OR=0.379, 95% CI=1.171-2.839, P <0.001, and OR=2.727, 95% CI=1.251-5.945, P <0.001, respectively).Changes in OCT3 levels appear to be associated with HCC. Also, changing the methylation pattern of this gene can reveal HCC pathology.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Correlation between organic cation transporter gene polymorphisms and the toxicities and clinical response of oxaliplatin / 中国临床药理学与治疗学

AIM: To investigate the relationship between genotypes of rs628031, rs650284, rs683369 of SLC22A1 gene and the toxicities and clinical response of oxaliplatin in patients with colorectal cancer. METHODS: A total of 72 patients diagnosed as colorectal cancer during January 2018 to June 2018 were selected and all patients received oxaliplatin treatment. Their peripheral venous blood was collected and genotyping was conducted by using SNaPshot. The toxicities including gastrointestinal toxicity, hematological toxicity and peripheral neurotoxicity were evaluated according to the Common Terminology Criteria Adverse Events (CTCAE) Version 5.0. Clinical response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1). RESULTS: The results of Chi-test showed that different genotypes of SLC22A1 SNP sites rs628031 and rs683369 may be related to the toxicities and clinical response of oxaliplatin significantly. Specifically, when compared with the patients with GG type of rs628031, the patients with the GA or AA type had a lower incidence of grade 3 nausea and vomiting (P=0.017) and may also be less responsive to efficacy (P=0.008). When compared with the patients with CC type of rs683369, the patients with the GC or GG type had a lower incidence of grade 3 nausea and vomiting (P=0.002) and may also be less responsive to efficacy (P=0.014).CONCLUSION: The polymorphisms of SLC22A1 gene are closely related to the toxicities and clinical response of oxaliplatin in patients with colorectal cancer, which may be helpful for improving clinical treatment.

Organic cation transporters in central nervous system diseases: research advances / 国际药学研究杂志

Organic cation transporters(OCT), one of the important members of membrane transporter family, can transport many kinds of positively charged substances and organic cation drugs used in physiological and pharmacological researches. A large number of studies have shown that the expression and function of OCT play an important role in the pathogenesis of some central nervous system(CNS)diseases, thus affecting the homeostasis of the internal environment. This article reviews the structure, substrate selectivity, tissue distribution and gene polymorphism of OCT in the CNS and provides a new possibility for the development of drugs targeting OCT and the clinical targeting of CNS diseases.

Effects of Radix Isatidis and contained indigo and indirubin on organic cation transporters OCT1 and OCT2 in mouse kidney / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of Radix Isatidis and its constituents indigo and in?dirubin on two principal subtypes of organic cation transporters(OCT)OCT1,OCT2 in vivo in mice. METHODS Decoction of Radix Isatidis (DRI) 1.6 and 6.4 g · kg-1,granules of Radix Isatidis (GRI) 0.615 and 2.460 g·kg-1,indigo 0.008 and 0.640 mg·kg-1 and indirubin 0.0192 and 1.536 mg·kg-1 were ig given to NIH mice(60 mice per group),twice a day for 5 d. Four control groups were set up,including the vehicle of water,0.5% sodium carboxymethyl cellulose(CMC),additives of sucrose plus dextrin (1.5 g · kg-1)and positive control quinidine(0.025 g · kg-1). Sixty minutes after the last dosing,all the mice were iv given metformin(Met)5 mg·kg-1,and at 1.0,2.5,5.0,7.5,10.0 and 20.0 min after Met iv,10 mice in each group were sacrificed to collect whole blood and kidneys respectively. The right kidney was homogenized for Met accumulation test and the left one used to extract total RNA for analysis of OCT1 and OCT2 mRNA expressions by real-time PCR. The contents of Met in sera and kidneys were quantified by HPLC. Major pharmacokinetic parameters of Met in sera were analyzed by pharmacokinetic software(DAS 2.0). RESULTS There was no significant difference between water control group,0.5%CMC group and sucrose plus dextrin group in any examined item. Compared with vehicle control group (water and 0.5%CMC group),all the related pharmacokinetic parameters in DRI 6.4 g · kg- 1,GRI 2.46 g · kg-1,indigo 0.640 mg · kg-1 and indirubin 1.536 mg · kg-1 groups were changed significantly (P<0.05,P<0.01). The elimination half time (t1/2β) was prolonged 13%-97%,volume of distribution reduced by 13%-72%,clearance(Cl)reduced by 9%-65%,and the area under the concentration-time curve (AUC0-20 min) increased by 13%-135%. AUC0-20 min obtained from renal Met accumulations was significantly increased(P<0.01)while Met uptake by kidney slices was reduced(P<0.05,P<0.01). The expressions of OCT1 and OCT2 mRNA were obviously down-regulated(P<0.05,P<0.01). CONCLUSION The mouse renal OCT1 and OCT2 are significantly inhibited by DRI,GRI,indigo and indirubin. The inhibitory effect of Radix Isatidis on OCT1 and OCT2 probably arises from indigo and indirubin contained.