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Cyclosporine A and PSC833 inhibits ABCA1 function via direct binding

Nagao, Kohjiro, Maeda, Minami, Manucat, Noyalyn B. and Ueda, Kazumitsu (2012) Cyclosporine A and PSC833 inhibits ABCA1 function via direct binding. Biochimica et Biophysica Acta, 1831 (2). pp. 398-406. ISSN 0006-3002


ATP-binding cassette protein A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL). However,
the detailed mechanism of HDL formation remains unclear; in order to reveal it, chemicals that specifically
block each step of HDL formation would be useful. Cyclosporine A inhibits ABCA1-mediated cholesterol efflux,
but it is not clear whether this is mediated via inhibition of calcineurin.We analyzed the effects of cyclosporine
A and related compounds on ABCA1 function in BHK/ABCA1 cells. Cyclosporine A, FK506, and pimecrolimus
inhibited ABCA1-mediated cholesterol efflux in a concentration-dependent manner, with IC50 of 7.6, 13.6, and
7.0 μM, respectively. AnmTOR inhibitor, rapamycin also inhibited ABCA1,with IC50 of 18.8 μM. The primary targets
for these drugswere inhibited at much lower concentrations in BHK/ABCA1 cells, suggesting that theywere
not involved. Binding of [3H] cyclosporine A to purified ABCA1 could be clearly detected. Furthermore, a
non-immunosuppressive cyclosporine, PSC833, inhibited ABCA1-mediated cholesterol efflux with IC50 of
1.9 μM, and efficiently competed with [3H] cyclosporine A binding to ABCA1. These results indicate that cyclosporine
A and PSC833 inhibit ABCA1 via direct binding, and that the ABCA1 inhibitor PSC833 is an excellent candidate
for further investigations of the detailed mechanisms underlying formation of HDL.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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