Araújo João R, Gonçalves Pedro, Martel Fátima
Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
Pharmacology. 2009;83(3):170-6. doi: 10.1159/000192587. Epub 2009 Jan 15.
Folic acid (FA) is an essential micronutrient that is particularly important during pregnancy for normal placental and fetal development and growth. The placenta and the fetus become frequently exposed to drugs of abuse such as cannabinoids because of maternal use of these substances. The aim of this study was to investigate the influence of cannabinoids on the uptake of FA by BeWo cells. Acute treatment with anandamide (1-10 micromol/l) caused a 15% decrease in (3)H-FA uptake at pH 7.5. Moreover, tetrahydrocannabinol (THC) (1-10 micromol/l) caused a 30% increase, and AM630 (1 mumol/l) a 15% decrease in this parameter at pH 6.5. Neither the inhibitory effect of anandamide nor the stimulatory effect of THC were changed in the presence of cannabi- noid receptor type 1 or type 2 antagonists (AM251 and AM630, respectively). Chronic treatment (48 h) with THC (100 nmol/l) and AM251 (100 nmol/l) decreased the uptake of (3)H-FA by 20% at pH 7.5, and anandamide (1 micromol/l) and AM630 (10-500 nmol/l) increased it by 30%. Moreover, CP55,940 (10 nmol/l) increased the uptake of (3)H-FA by 30% at pH 6.5. RT-PCR analysis showed that the mRNA levels of the reduced folate transporter 1 increased by 9% after chronic treatment with AM630 (500 nmol/l). The mRNA levels of the proton-coupled folate transporter decreased by 17% and increased by 18% after chronic treatment with THC (0.1 mumol/l) and AM251 (100 nmol/l), respectively. In conclusion, (3)H-FA uptake by BeWo cells is significantly, although not very markedly, changed by several distinct CB receptor agonists and antagonists, both after acute and chronic exposure of the cells. The acute effects of cannabinoid receptor agonists do not seem to be mediated by the cannabinoid receptor, and with a few exceptions the chronic effects do not seem to be related to changes in the expression levels of FA transporters.
叶酸（FA）是一种必需的微量营养素，在孕期对胎盘和胎儿的正常发育及生长尤为重要。由于母体使用大麻素等药物，胎盘和胎儿经常会接触到这类滥用药物。本研究的目的是调查大麻素对BeWo细胞摄取FA的影响。在pH 7.5条件下，用花生四烯乙醇胺（1 - 10微摩尔/升）进行急性处理，导致³H - FA摄取量下降15%。此外，在pH 6.5条件下，四氢大麻酚（THC）（1 - 10微摩尔/升）使该参数增加30%，而AM630（1微摩尔/升）使其下降15%。在存在1型或2型大麻素受体拮抗剂（分别为AM251和AM630）的情况下，花生四烯乙醇胺的抑制作用和THC的刺激作用均未改变。用THC（100纳摩尔/升）和AM251（100纳摩尔/升）进行慢性处理（48小时），在pH 7.5条件下使³H - FA摄取量下降20%，而花生四烯乙醇胺（1微摩尔/升）和AM630（10 - 500纳摩尔/升）使其增加30%。此外，在pH 6.5条件下，CP55,940（10纳摩尔/升）使³H - FA摄取量增加30%。逆转录聚合酶链反应（RT - PCR）分析表明，用AM630（500纳摩尔/升）进行慢性处理后，还原型叶酸转运蛋白1的mRNA水平增加了9%。在用THC（0.1微摩尔/升）和AM251（100纳摩尔/升）进行慢性处理后，质子偶联叶酸转运蛋白的mRNA水平分别下降了17%和增加了18%。总之，无论是急性还是慢性暴露于细胞后，几种不同的CB受体激动剂和拮抗剂均会显著（尽管不是非常明显）改变BeWo细胞对³H - FA的摄取。大麻素受体激动剂的急性作用似乎不是由大麻素受体介导的，并且除了少数例外情况，慢性作用似乎与FA转运蛋白表达水平的变化无关。
