Polished rice as natural sources of cancer-preventing geranylgeranoic acid

Abstract

Geranylgeranoic acid, a 20-carbon polyprenoic acid (all-trans 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecatetraenoic acid) and its derivatives were previously developed as synthetic “acyclic retinoids” for cancer chemoprevention. Recently, we demonstrated the natural occurrence of geranylgeranoic acid in various medicinal herbs (Shidoji and Ogawa, 2004). In this present study, we present several lines of evidence to demonstrate that geranylgeranyl diphosphate taken in foods could be metabolized to GGA through geranylgeraniol and geranylgeranyl aldehyde via the following steps: 1) The conversion from geranylgeranyl diphosphate to geranylgeraniol was demonstrated to occur by the action of bovine intestinal alkaline phosphatase, with a Km of 46.1 µM. 2) Geranylgeraniol oxidase-mediated conversion of geranylgeraniol to geranylgeranyl aldehyde was revealed in rat liver homogenates, which activity was mainly localized in the mitochondrial fraction. The mitochondrial enzyme showed a Km of 92.9 µM. 3) The conversion of geranylgeranyl aldehyde to geranylgeranoic acid by geranylgeranyl aldehyde dehydrogenase in rat liver homogenates was absolutely dependent on exogenously added NAD+ or NADP+. The Km of the mitochondrial geranylgeranyl aldehyde dehydrogenase was 27.5 µM for geranylgeranyl aldehyde. Taken together, our data suggest that cancer preventive geranylgeranoic acid could be a physiological metabolite from commonly consumed foods.

Unequivocal evidence for endogenous geranylgeranoic acid biosynthesized from mevalonate in mammalian cells

“…Consistently, Holstein et al (41) reported that the FPP levels were higher than the geranyl diphosphate levels in human myeloma cell lines. Taken together with our previous reports (26,27), we propose a possible metabolic flow from MVA to GGA in Fig. 7, where GGOH, a dephosphorylated form of GGPP by GGPP pyrophosphatase (25), is enzymatically oxidized by using molecular oxygen to GGal (26), which is further oxidized to GGA in a NAD-dependent manner (26,27).…”

“…Once geranylgeraniol (GGOH) is produced through dephosphorylation of GGPP by the specific diphosphatase, it seems reasonable to assume that the nonspecific fatty alcohol dehydrogenase-fatty aldehyde dehydrogenase system might produce GGA through an intermediate of geranylgeranial (GGal). However, we found that the first oxidation reaction from GGOH to GGal did not require NAD + , but requires molecular oxygen, at least in a cell-free system of either HuH-7 cell lysates (26) or rat liver homogenates (27). At present, the GGA biosynthetic pathway from GGOH is not yet clear, but we have preliminarily reported the natural existence of endogenous GGA in human hepatoma HuH-7 cells (26) and also in blood serum from healthy young volunteers (28) using LC/MS.…”

Geranylgeraniol oxidase activity involved in oxidative formation of geranylgeranoic acid in human hepatoma cells

“…We assigned the latter peak as GGal, because authentic or freshly prepared GGal eluted at 27.5 min corresponding to the latter peak, but aged GGal preparation yielded additional 26.5-min peak. These two peaks were also previously detected on a HPLC chromatogram of UV absorption at 250 nm with rat liver homogenates (14). When NAD was removed from the reaction mixture, to our surprise, both peak areas increased (Fig.…”

“…Based upon its chemical structure, we reasonably assumed that cancer-preventive GGA could be enzymatically derived from GGOH, which is a common precursor of all natural diterpenoids hydrolyzed from GGPP by a specific pyrophosphatase enzyme (2,12). We have also reported that bovine intestinal alkaline phosphatase releases GGOH from GGPP (14). We wished to know whether GGOH is oxidized to GGA in human cells, because GGA has been shown to be a biologically active compound that can induce cell death in human hepatoma cells (16).…”

Geranylgeraniol Induces PPARγ Expression and Enhances the Biological Effects of a PPARγ Agonist in Adipocyte Lineage Cells

“…Geranylgeraniol (GGOH) is a C20 isoprenoid found in fruits, vegetables, and grains, including rice. As a food substance, GGOH is categorized as 'Generally Recognized as Safe' (8). GGOH is an intermediate product in the mevalonate pathway and acts as a precursor to geranylgeranylpyrophosphate (GGPP).…”