Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid

Abstract

The ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) is an efflux protein involved in the bioavailability and milk secretion of endogenous and exogenous compounds, actively affecting milk composition. A limited number of physiological substrates have been identified. However, no studies have reported the specific effect of this polymorphism on the secretion into milk of compounds implicated in milk quality such as vitamins or endogenous compounds. The bovine ABCG2 Y581S polymorphism is described as a gain-of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates. This work aims to study the impact of Y581S polymorphism on plasma disposition and milk secretion of compounds such as riboflavin (vitamin B 2 ), enterolactone, a microbiota-derived metabolite from the dietary lignan secoisolariciresinol and uric acid. In vitro transport of these compounds was assessed in MDCK-II cells overexpressing the bovine ABCG2 (WT-bABCG2) and its Y581S variant (Y581S-bABCG2). Plasma and milk levels were obtained from Y/Y homozygous and Y/S heterozygous cows. The results show that riboflavin was more efficiently transported in vitro by the Y581S variant, although no differences were noted in vivo. Both uric acid and enterolactone were substrates in vitro of the bovine ABCG2 variants and were actively secreted into milk with a two-fold increase in the milk/plasma ratio for Y/S with respect to Y/Y cows. The in vitro ABCG2-mediated transport of the drug mitoxantrone, as a model substrate, was inhibited by enterolactone in both variants, suggesting the possible in vivo use of this enterolignan to reduce ABCG2-mediated milk drug transfer in cows. The Y581S variant was inhibited to a lesser extent probably due to its higher transport capacity. All these findings point to a significant role of the ABCG2 Y581S polymorphism in the milk disposition of enterolactone and the endogenous molecules riboflavin and uric acid, which could affect both milk quality and functionality.

Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk

“…ABCG2 plays an important role in uric acid transfer into milk, since its secretion was increased in dairy cow carriers of the Y581S polymorphism [150]. As suggested by the authors, the presence of this compound could affect the redox potential of milk.…”

A Review of Lignan Metabolism, Milk Enterolactone Concentration, and Antioxidant Status of Dairy Cows Fed Flaxseed

“…It was further demonstrated that the milk-to-plasma ratio of EL decreased significantly in the Abcg2 (−/−) knockout female mice phenotype compared with the wild-type group (0.4 vs. 6.4) [62]. A subsequent study showed that EL was used as substrate to the bovine ABCG2 variant Y in vitro and was also actively secreted in milk resulting in a 2-fold increase in its milk-to-plasma ratio in Y/S heterozygous versus Y/Y homozygous cows [66]. The bovine ABCG2 Y581S variant has been described as a gain-of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates [67,68,69].…”

Widespread cis-regulation of RNA-editing in a large mammal

“…Edited sites were also observed in STAT5A and STAT5B, comprising transcription factors with critical roles in mammary differentiation and lactation (Liu et al, 1995;Cui et al, 2004). A number of other edited genes are important mediators of milk fat synthesis (LPL, ACACA, GPAM (Bionaz and Loor, 2008)) and secretion (XDH, PLIN3 (Bionaz and Loor, 2008)), or are involved in the transport of small molecules in milk: SLC37A1 (Pan et al, 2011), ABCG2 (Otero et al, 2016). Together, these genes represent some of the most prominent and well-published genes in lactation biology, and include many of the largest effect loci implicated in genetic regulation of these traits (He et al, 2011;Khatib et al, 2008;Bionaz and Loor, 2008;Kemper et al, 2016;Olsen et al, 2007).…”