title: Probucol-Oxidized Products, Spiroquinone and Diphenoquinone, Promote Reverse Cholesterol Transport in Mice.
abstract: OBJECTIVE
  Oxidized products of probucol, spiroquinone and diphenoquinone, were shown to increase cell cholesterol release and plasma high-density lipoprotein (HDL) by inhibiting degradation of ATP-binding cassette transporter A1. We investigated whether these compounds enhance reverse cholesterol transport in mice.
  
  
  RESULTS
  Spiroquinone and diphenoquinone increased ATP-binding cassette transporter A1 protein (2.8- and 2.6-fold, respectively, P<0.01) and apolipoprotein A-I-mediated cholesterol release (1.4- and 1.4-fold, P<0.01 and P<0.05, respectively) in RAW264.7 cells. However, diphenoquinone, but not spiroquinone, enhanced cholesterol efflux to HDL (+12%, P<0.05), whereas both increased ATP-binding cassette transporter G1 protein, by 1.8- and 1.6-fold, respectively. When given orally to mice, both compounds significantly increased plasma HDL-cholesterol, by 19% and 20%, respectively (P<0.05), accompanied by an increase in hepatic and macrophage ATP-binding cassette transporter A1 but not ATP-binding cassette transporter G1. We next evaluated in vivo reverse cholesterol transport by injecting RAW264.7 cells labeled with (3)H-cholesterol intraperitoneally into mice. Both spiroquinone and diphenoquinone increased fecal excretion of the macrophage-derived (3)H-tracer, by 25% and 28% (P<0.01 and P<0.05), respectively. spiroquinone/diphenoquinone did not affect fecal excretion of HDL-derived (3)H-cholesterol, implying that macrophage-to-plasma was the most important step in spiroquinone/diphenoquinone-mediated promotion of in vivo reverse cholesterol transport. Finally, spiroquinone significantly reduced aortic atherosclerosis in apolipoprotein E null mice when compared with the vehicle.
  
  
  CONCLUSIONS
  Spiroquinone and diphenoquinone increase functional ATP-binding cassette transporter A1 in both the macrophages and the liver, elevate plasma HDL-cholesterol, and promote overall reverse cholesterol transport in vivo. These compounds are promising as therapeutic reagents against atherosclerosis.
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Emi
authors: E
authors: Yakushiji
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.). ayaori@ba2.so-net.ne.jp.
authors: Makoto
authors: M
authors: Ayaori
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Takafumi
authors: T
authors: Nishida
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Kazusa
authors: K
authors: Shiotani
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Shunichi
authors: S
authors: Takiguchi
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Kazuhiro
authors: K
authors: Nakaya
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Harumi
authors: H
authors: Uto-Kondo
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Masatsune
authors: M
authors: Ogura
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Makoto
authors: M
authors: Sasaki
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Makiko
authors: M
authors: Yogo
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Tomohiro
authors: T
authors: Komatsu
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Rui
authors: R
authors: Lu
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Shinji
authors: S
authors: Yokoyama
authors: From the Division of Anti-Aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (E.Y., M.A., T.N., K.S., S.T., K.N., H.U.-K., M.O., M.S., M.Y., T.K., K.I.); and Nutritional Health Science Research Center, Chubu University, Kasugai, Japan (R.L., S.Y.).
authors: Katsunori
authors: K
authors: Ikewaki
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000187:drug effects* / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000097:blood; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D058226:Plaque, Atherosclerotic; D011341:Probucol / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000730:Androstadienes; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002784:Cholesterol; D008076:Cholesterol, HDL; D011341:Probucol; D011809:Quinones; C577833:Abca1 protein, mouse; C001081:diphenoquinone; C035143:spirorenone
keywords: HDL-cholesterol; apolipoprotein A-I; diphenoquinone; macrophage; probucol