Induction of ABCG2/BCRP restricts the distribution of zidovudine to the fetal brain in rats

Abstract

Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.

An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus

“…The expression of Abcg2 mRNA in the Wistar rat fetal brain was ~5 times higher than the maternal brain on gestation day 20, and decreased to nearly the same levels as the dam upon birth [109,111,112]. In a recent study with pregnant Sprague-Dawley rats, chronic administration of the antiviral drug zidovudine over gestation significantly induced Bcrp protein expression in the placenta and fetal brain and this induction of Bcrp was accompanied with a significant reduction in fetal brain concentration of zidovudine after a single dose intravenous administration, and the activity of Bcrp was inhibited by a Bcrp inhibitor [113]. These results suggest that Bcrp can limit drug exposure to the fetal brain, and the degree of toxicity may be affected by inhibition of Bcrp at both the BBB of the fetus and the placental barrier.…”

“…As reviewed in this article, due to their substantial and strategical expression in the placenta, P-gp and BCRP have been shown to limit fetal exposure to drugs and xenobiotics in vivo primarily in animal models. However, up to date, only a few studies have directly linked P-gp or BCRP in the placenta with fetal toxicity of drugs and xenobiotics [57,113,140,141]. Future studies should be more focused on understanding how P-gp and BCRP influence the toxicity of drugs and xenobiotics to the developing fetus.…”

“…Few studies have examined P-gp and BCRP activities in fetal tissues. A recent study showed that chronic administration of zidovudine to pregnant rats markedly induced Bcrp in the fetal brain and placenta, which was accompanied with no significant effects on mitochondrial functionality of the fetal brain [113]. Thus, Bcrp induction appears to protect the fetal brain from zidovudine toxicity.…”

Cerebral Vascular Toxicity of Antiretroviral Therapy

“…For instance, the findings of a recent study on prophylactic AZT administration suggests that the mechanism behind increased mitochondrial brain toxicity in some individuals, but not in others, could be explained through differential activity of the ATP-binding cassette efflux transporters which influence the transfer of AZT to the brain. These interactions may be influenced via genetic, pathological or iatrogenic factors, consequently increasing the antiretroviral-induced mitochondrial toxic effects on the brain tissue (Filia et al 2017).…”

Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain

“…AZT is the substrate of BCRP [ 8 , 9 ], which explains its characteristics of low permeability [ 10 , 11 ]. Although the roles of BCRP in the brain distribution of AZT have not been confirmed in Abcg2 −/− mice [ 12 ], low mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT is attributed to low accumulation of AZT in tissues that is at least partly due to BCRP overexpression [ 13 ]. We previously reported that liver failure induced by thioacetamide or bile-duct ligation (BDL) impaired the function and expression of BCRP in the BBB of animals, leading to increased distribution of its substrates in the brain [ 14 – 16 ].…”