Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas, Kansas City, MO, USA.
Free Radic Res. 2020 Jul;54(7):525-534. doi: 10.1080/10715762.2020.1812597. Epub 2020 Sep 1.
Slc7a11 (xCT) and Slc3a1 (rBAT) are cystine uptake transporters that maintain intracellular concentrations of cysteine, the rate-limiting amino acid in glutathione synthesis. This study was conducted to first determine the tissue distribution of the two transporters in male and female mice. Because Slc3a1 was the primary cystine transporter in liver, its sex-divergent expression, ontogeny, diurnal rhythm and whether its mRNA expression is altered by transcription factors (AhR, CAR, PXR, PPARα, and Nrf2) was also investigated. Slc7a11 was expressed highest in brain and gonads. Slc3a1 was expressed highest in kidney and intestine, followed by liver. Duodenal and hepatic Slc3a1 was higher in females than males. Hepatic Slc3a1 was high during darkness and low during daytime. Hepatic Scl3a1 was lowest pre-birth, increased to near maximal levels at birth, decreased back to pre-birth levels between Days 3-10, and then returned to peak levels by Day 45. Except for CAR, activation of transcription factors did not increase hepatic mRNA expression of Slc3a1. Chemical activation of CAR significantly induced Slc3a1 1.4-fold in wild-type but not CAR-null mice. Slc3a1 mRNA was higher in livers of AhR- and Nrf2-null mice compared to wild-type mice. High doses of diquat but not acetaminophen induced Slc3a1, suggesting Slc3a1 may respond to oxidative stress but not necessarily to GSH depletion. Overall, Slc7a11 is mainly expressed in brain and gonads, whereas Slc3a1 is mainly expressed in kidney, small intestine and liver, and its hepatic expression is regulated by diurnal rhythm and certain xenobiotic treatments.
Slc7a11（xCT）和 Slc3a1（rBAT）是胱氨酸摄取转运体，可维持细胞内半胱氨酸的浓度，半胱氨酸是谷胱甘肽合成的限速氨基酸。本研究首先确定了这两种转运体在雄性和雌性小鼠中的组织分布。由于 Slc3a1 是肝脏中胱氨酸的主要转运体，因此还研究了其性别差异表达、个体发生、昼夜节律以及其 mRNA 表达是否受转录因子（AhR、CAR、PXR、PPARα和 Nrf2）的改变。Slc7a11 在大脑和性腺中的表达最高。Slc3a1 在肾脏和肠道中的表达最高，其次是肝脏。十二指肠和肝脏 Slc3a1 在雌性中的表达高于雄性。肝脏 Slc3a1 在夜间较高，白天较低。肝脏 Slc3a1 在出生前最低，出生时接近最大水平，在第 3-10 天降至出生前水平，然后在第 45 天恢复到峰值水平。除了 CAR 之外，转录因子的激活并未增加肝脏 Slc3a1 的 mRNA 表达。CAR 的化学激活使野生型小鼠的 Slc3a1 增加了 1.4 倍，但在 CAR 缺失型小鼠中没有增加。与野生型小鼠相比，AhR 和 Nrf2 缺失型小鼠肝脏中的 Slc3a1 mRNA 水平更高。高剂量百草枯而不是对乙酰氨基酚诱导 Slc3a1，表明 Slc3a1 可能对氧化应激有反应，但不一定对 GSH 耗竭有反应。总体而言，Slc7a11 主要在大脑和性腺中表达，而 Slc3a1 主要在肾脏、小肠和肝脏中表达，其肝脏表达受昼夜节律和某些外源物处理的调节。
