Gender-specific expression of ATP-binding cassette ( Abc ) transporters and cytoprotective genes in mouse choroid plexus

Abstract

The choroid plexus (CP) and blood-brain barrier (BBB) control the movement of several drugs and endogenous compounds between the brain and systemic circulation. The multidrug resistance associated protein (Mrp) efflux transporters form part of these barriers. Several Mrp transporters are positively regulated by the transcription factor nuclear factor erythroid-2-related factor (Nrf2) in liver. The Mrps, Nrf2 and Nrf2-dependent genes are cytoprotective and our aim was to examine basal gender differences in expression of Mrp transporters, Nrf2 and Nrf2-dependent genes (Nqo1 and Ho-1) in the brain-barriers. Previous studies have shown higher expression of Mrp1, Mrp2 and Mrp4 in female mouse liver and kidney. We hypothesized that similar renal/hepatic gender-specific patterns are present in the brain-barrier epithelia interfaces. qPCR and immunoblot analyses showed that Mrp4, Ho-1 and Nqo1 expression was higher in female CP. Mrp1, Mrp2 and Nrf2 expression in the CP had no gender pattern. Female Mrp1, Mrp2 and Mrp4 mouse brain expressions in remaining brain areas, excluding CP, were higher than male. Functional analysis of Mrp4 in CP revealed active accumulation of the Mrp4 model substrate fluo-cAMP. WT female CP had 10-fold higher accumulation in the vascular spaces than males and 60% higher than Mrp4−/− females. Probenecid blocked all transport. Methotrexate did as well except in Mrp4−/− females where it had no effect, suggesting compensatory induction of transport occurred in Mrp4−/−. Collectively, our findings indicate significant gender differences in expression of Mrp transporters and cytoprotective genes in the CP and BBB.

Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide

“…Previous transcriptomic studies have also shown that over the period of 6–21 weeks of age the only difference in ABC transporters expression is a very minor increase of MRP1 (p = 0.04; FC = 1.05; supplementary dataset) 29 . Some previous studies in rodents have indicated that ABC-transporter expression at blood-brain and blood-CSF interfaces may be different between sexes 30 . However other transcriptomic studies have established that for both P14 and 6 weeks adult rats there are no statistically significant differences in ABC transporter expression in the brain between male and female animals 29 .…”

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

“…The ABC-type transporters act as gatekeepers by allowing or limiting the entrance of a wide variety of substrates across cellular membranes (6). A total of 51 ABC transporter genes have been identified and are grouped into seven subfamilies, namely A-G, based on their phylogenetic distance (7).…”

Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain

“…Higher relative expression of Abcg2, Abcc1, and Slc29a1 in the placentas of female compared with male fetuses was identified at the mRNA level in this model, emphasizing the role of sex in modulating transporter expression. Sex differences in ATP-binding cassette transporter expression have been described elsewhere [30,64], and are well established in adult rodent and human tissues (though not in the placenta), often demonstrating higher transporter expression and activity in females compared with males for rodent efflux transporters including P-gp [65], and Mrps [59,64]. In-vitro modulation of placental transporter expression by sex hormones, such as 17b-estradiol has also been demonstrated for P-gp and Bcrp [66][67][68]; however, findings of sex-differential transporter expression in an in-vivo model of antiretroviral therapy is novel, and in the context of existing research in in-vitro systems, suggests that differences in transporter expression may be influenced by sex differences in fetal endocrine environment.…”