Roles of rat and human aldo-keto reductases in metabolism of farnesol and geranylgeraniol.
Roles of rat and human aldo-keto reductases in metabolism of farnesol and geranylgeraniol.
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DOI：
10.1016/j.cbi.2010.12.017
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发表时间：
2011-05-30
影响因子：
5.1
通讯作者：
Nara, Akira
中科院分区：
文献类型：
--
作者：
Endo, Satoshi;Matsunaga, Toshiyuki;Ohta, Chisato;Soda, Midori;Kanamori, Ayano;Kitade, Yukio;Ohno, Satoshi;Tajima, Kazuo;El-Kabbani, Ossama;Nara, Akira
法尼醇（FOH）和香叶基香叶醇（GGOH）具有多种生物学作用，由甲羟戊酸途径产生，并通过醛类中间体（法尼醛和香叶基香叶醛）分别分解代谢为法尼酸和香叶基香叶酸。我们研究了在大鼠组织中负责代谢步骤的氧化还原酶的细胞内分布、序列和性质。FOH和GGOH氧化成醛中间体主要由醇脱氢酶1（在肝脏和结肠中）和7（在胃和肺中）介导，随后的步骤由微粒体醛脱氢酶催化。此外，在肝外组织的细胞质中检测到催化醛中间体转化为FOH（或GGOH）的高还原酶活性，其中主要还原酶被鉴定为醛酮还原酶（AKR）1C 15。具有相似特异性的人还原酶被鉴定为AKR 1B 10和AKR 1C 3，其在AKR 1A-1C亚家族的七种酶中最有效地还原法尼醛和香叶基香叶醛。在培养的细胞中，从FOH到法呢酸的总代谢显著降低AKR 1C 15的过表达，并增加添加AKR 1C 3抑制剂，托芬那酸和R-氟比洛芬。因此，AKR（大鼠中的1C 15，以及人类中的1B 10和1C 3）可能在控制FOH和GGOH的生物利用度方面发挥重要作用。
Farnesol (FOH) and geranylgeraniol (GGOH) with multiple biological actions are produced from the mevalonate pathway, and catabolized into farnesoic acid and geranylgeranoic acid, respectively, via the aldehyde intermediates (farnesal and geranylgeranial). We investigated the intracellular distribution, sequences and properties of the oxidoreductases responsible for the metabolic steps in rat tissues. The oxidation of FOH and GGOH into their aldehyde intermediates were mainly mediated by alcohol dehydrogenases 1 (in the liver and colon) and 7 (in the stomach and lung), and the subsequent step into the carboxylic acids was catalyzed by a microsomal aldehyde dehydrogenase. In addition, high reductase activity catalyzing the aldehyde intermediates into FOH (or GGOH) was detected in the cytosols of the extra-hepatic tissues, where the major reductase was identified as aldo-keto reductase (AKR) 1C15. Human reductases with similar specificity were identified as AKR1B10 and AKR1C3, which most efficiently reduced farnesal and geranylgeranial among seven enzymes in the AKR1A-1C subfamilies. The overall metabolism from FOH to farnesoic acid in cultured cells was significantly decreased by overexpression of AKR1C15, and increased by addition of AKR1C3 inhibitors, tolfenamic acid and R-flurbiprofen. Thus, AKRs (1C15 in rats, and 1B10 and 1C3 in humans) may play an important role in controlling the bioavailability of FOH and GGOH.
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DOI：
10.1016/s0304-4165(96)00126-2
发表时间：
1997-04-17
影响因子：
3
作者：
Kelson, TL;McVoy, JRS;Rizzo, WB
通讯作者：
Rizzo, WB
DOI：
10.1111/j.1432-1033.1987.tb10559.x
发表时间：
1987-01-02
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
JULIA, P;FARRES, J;PARES, X
通讯作者：
PARES, X
影响因子：
1.7
作者：
Kodaira, Yuichi;Kusumoto, Takeru;Sagami, Hiroshi
通讯作者：
Sagami, Hiroshi
影响因子：
3.9
作者：
BANSAL, VS;VAIDYA, S
通讯作者：
VAIDYA, S
影响因子：
2.7
作者：
Gobec, S;Brozic, P;Rizner, TL
通讯作者：
Rizner, TL