GHB toxicokinetics and renal monocarboxylate transporter expression are influenced by the estrus cycle in rats.
GHB toxicokinetics and renal monocarboxylate transporter expression are influenced by the estrus cycle in rats.
复制标题
DOI：
10.1186/s40360-023-00700-y
复制
发表时间：
2023-11-02
影响因子：
2.9
通讯作者：
中科院分区：
文献类型：
--
作者：
非法使用和滥用伽马-羟丁酸是由于其镇静/催眠和欣快作用。目前，临床上没有治疗GHB过量的疗法，护理重点是症状治疗，直到药物从体内消除。质子和钠依赖性单羧酸转运蛋白（MCT（SLC 16 A）和SMCT（SLC 5A））转运并介导GHB的肾脏清除和分布。以前，已经表明MCT表达受肝脏、骨骼肌和Sertoli细胞中的性激素调节。本研究的重点是评估GHB毒代动力学和肾脏单羧酸转运蛋白的表达在女性的发情周期，在男性和女性性激素的情况下。在发情周期内的雌性大鼠以及卵巢切除（OVX）雌性、雄性和去势（CST）雄性大鼠中评价了GHB毒代动力学和MCT 1、SMCT 1和CD 147的肾脏转运蛋白表达。静脉推注GHB（600和1000 mg/kg），并在给药后6小时收集血浆和尿液样本。使用经验证的LC/MS/MS测定法定量GHB浓度。通过qPCR和蛋白质印迹定量转运蛋白mRNA和蛋白质表达。GHB肾清除率和AUC在不同性别之间和整个发情周期内均存在差异，与雄性（完整和CST）和OVX雌性相比，发情前期雌性的肾清除率较高，AUC较低。我们证明了肾脏MCT 1膜表达在发情周期中变化，在发情前期雌性中观察到最低表达，这与观察到的GHB肾脏清除率变化一致。我们的研究结果表明，女性可能不太容易受到GHB诱导的毒性，这是由于肾脏MCT 1表达降低导致肾脏清除率增加导致暴露量降低。在线版本包含补充材料，可通过10.1186/s40360-023-00700-y获得。
The illicit use and abuse of gamma-hydroxybutyric acid (GHB) occurs due to its sedative/hypnotic and euphoric effects. Currently, there are no clinically available therapies to treat GHB overdose, and care focuses on symptom treatment until the drug is eliminated from the body. Proton- and sodium-dependent monocarboxylate transporters (MCTs (SLC16A) and SMCTs (SLC5A)) transport and mediate the renal clearance and distribution of GHB. Previously, it has been shown that MCT expression is regulated by sex hormones in the liver, skeletal muscle and Sertoli cells. The focus of the current study is to evaluate GHB toxicokinetics and renal monocarboxylate transporter expression over the estrus cycle in females, and in the absence of male and female sex hormones. GHB toxicokinetics and renal transporter expression of MCT1, SMCT1 and CD147 were evaluated in females over the estrus cycle, and in ovariectomized (OVX) female, male and castrated (CST) male rats. GHB was administered iv bolus (600 and 1000 mg/kg) and plasma and urine samples were collected for six hours post-dose. GHB concentrations were quantified using a validated LC/MS/MS assay. Transporter mRNA and protein expression was quantified by qPCR and Western Blot. GHB renal clearance and AUC varied between sexes and over the estrus cycle in females with higher renal clearance and a lower AUC in proestrus females as compared to males (intact and CST), and OVX females. We demonstrated that renal MCT1 membrane expression varies over the estrus cycle, with the lowest expression observed in proestrus females, which is consistent with the observed changes in GHB renal clearance. Our results suggest that females may be less susceptible to GHB-induced toxicity due to decreased exposure resulting from increased renal clearance, as a result of decreased renal MCT1 expression. The online version contains supplementary material available at 10.1186/s40360-023-00700-y.
登录
查看更多内容
DOI：
10.1111/j.1600-0854.2010.01155.x
发表时间：
2011-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Castorino JJ;Deborde S;Deora A;Schreiner R;Gallagher-Colombo SM;Rodriguez-Boulan E;Philp NJ
通讯作者：
Philp NJ
影响因子：
2.3
作者：
Corkery, John M.;Loi, Barbara;Schifano, Fabrizio
通讯作者：
Schifano, Fabrizio
影响因子：
3.4
作者：
Gopal, E.;Umapathy, N. S.;Prasad, P. D.
通讯作者：
Prasad, P. D.
影响因子：
--
作者：
Manente, Arcangela G.;Pinton, Giulia;Moro, Laura
通讯作者：
Moro, Laura
影响因子：
3.9
作者：
Cui, Dapeng;Morris, Marilyn E.
通讯作者：
Morris, Marilyn E.