Roles of rat and human aldo–keto reductases in metabolism of farnesol and geranylgeraniol

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 distributi...

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Published in:Chemico-biological interactions 2011-05, Vol.191 (1), p.261-268
Main Authors: Endo, Satoshi, Matsunaga, Toshiyuki, Ohta, Chisato, Soda, Midori, Kanamori, Ayano, Kitade, Yukio, Ohno, Satoshi, Tajima, Kazuo, El-Kabbani, Ossama, Hara, Akira
Format: Article
Language:English
Subjects:
AKR1C15
AKR1C3
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehydes - metabolism
Animals
bioavailability
carboxylic acids
Cell Line
colon
cultured cells
Cytosol - enzymology
Diterpenes - metabolism
Farnesol
Farnesol - metabolism
Geranylgeraniol
Humans
liver
metabolism
Microsomes - enzymology
oxidation
Oxidoreductases - metabolism
Rats
stomach
Terpenes - chemistry
Terpenes - metabolism
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Summary: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.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2010.12.017