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Febuxostat inhibited axillary osmidrosis risk factor ATP‐binding cassette transporter C11 in vitro

Dear Editor, Human ATP-binding cassette transporter C11 (ABCC11) is a risk factor of axillary osmidrosis (AO) that is characterized by unpleasant body odor from the armpits. The inhibition of ABCC11 is expected to be useful to overcome AO; however, no ABCC11 inhibitor is currently used clinically. Humans produce body odor like other animals. Nonetheless, in human culture, strong or specific body odors are sometimes perceived as undesirable. Among them, AO is a chronic skin condition characterized by unpleasant body odors and excessive sweating from the armpits. As is often the case in Asian countries such as Japan and China, in which people with strong body odor comprise a minor section of the population, AO tends to be more strongly disliked and is recognized as a disease. However, except for surgical treatments, there has been no causal therapy for AO. Thus, there is an unmet medical need for the development of a therapy for this unpleasant condition. Axillary osmidrosis risk is determined by a non-synonymous single nucleotide polymorphism, c.538G>A (p.Gly180Arg), in the ABCC11 gene. Biochemical analyses have revealed that this amino acid substitution (variant type, Arg180) enhances proteasomal degradation of de novo synthesized ABCC11 protein, which results in the loss of the cellular function of ABCC11. As genetically ABCC11-deficient subjects have little risk of AO, and functional ABCC11 (wild-type, Gly180) is present in the axillary apocrine glands that secrete a variety of odor precursors, it seems that the inhibition of ABCC11 function may be able to contribute to the prevention and treatment of AO. However, this notion has not yet been demonstrated because clinical investigations have been difficult due to the absence of ABCC11 inhibitors that have been approved for clinical use. Additionally, contrary to humans, rodents such as mice and rats have no Abcc11 gene; thus, it is almost impractical to examine the physiological impact of ABCC11 inhibition through in vivo experiments. Therefore, the investigation of ABCC11 inhibitors with biological safety is an important issue. In this study, we conducted an in vitro transport assay using ABCC11-expressing plasma membrane vesicles to explore ABCC11 inhibitors. We identified febuxostat, a non-purine selective inhibitor of xanthine oxidase developed for hyperuricemia management, as a novel ABCC11 inhibitor (Fig. 1). Detailed information on our methods, including critical materials and resources we used (Table S1), is available in Appendix S1. Briefly, plasma membrane vesicles were prepared from adenovirus-mediated transiently ABCC11-expressing 293A cells. Immunoblotting and an in vitro transport assay for [1,2,6,7-H(N)]-dehydroepiandrosterone sulfate (DHEA-S) an ABCC11 substrate, were conducted as described previously. To confirm the experimental system, we first examined ABCC11 expression on the plasma membrane vesicles (Fig. 1a), ATP-dependent DHEA-S transport into the ABCC11expressing plasma membrane vesicles (Fig. 1b) and time profile for ABCC11-mediated DHEA-S transport (Fig. 1c). As febuxostat inhibited ABCC11 in our preliminary screening, we further examined the concentration-dependent inhibitory effects of febuxostat on ABCC11 (Fig. 1d). The half maximal inhibitory concentration value of febuxostat against the ABCC11-mediated DHEA-S transport activity was 3.26 lmol/L. Additionally, at this concentration (3.26 lmol/L), febuxostat had little effect on the transport activity of ABCC2 (Fig. S1), which belongs to the same protein family as ABCC11. We herein demonstrated that febuxostat, a globally used drug for hyperuricemia treatment, is a novel ABCC11 inhibitor (Fig. 1). To the best of our knowledge, this is the first report of ABCC11 inhibition by a drug approved for clinical use on the market. As human axillary apocrine glands open into the hair follicles, the dermal administration of febuxostat onto the armpits, such as through a medical cream, may inhibit ABCC11 in humans. For this to be effective, such treatment must ensure appropriate levels of febuxostat in the ABCC11-expressing apocrine glands. On the other hand, a previous study has shown that the maximum plasma unbound concentration of febuxostat is 0.126 lmol/L when administrated to healthy subjects at a dose of 40 mg once daily for up to 12 consecutive days, given that the unbound fraction of febuxostat is 0.022. This suggests that p.o. administrated febuxostat has little inhibitory effect on ABCC11 in current clinical situations under the assumption of a uniform of febuxostat level throughout the body. Based on this, our data should be interpreted carefully. However, despite the limitation on its practical use, our discovery will pave the way for the first proof of concept study in humans to investigate the effect of ABCC11 inhibition on the AO phenotype. Such study will be worth consideration in the