Tissue distribution, hormonal regulation, ontogeny, diurnal expression, and induction of mouse cystine transporters Slc3a1 and Slc7a9.

ABSTRACT

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.