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 K(m) 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 K(m) 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 K(m) 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.