Metabolism of [³H]farnesol to cholesterol and cholesterogenic intermediates in the living rat eye

Adult rats were injected intravitreally with all-trans [1-³H]farnesol, with or without co-injection of the squalene epoxidase inhibitor NB-598. Retinas were isolated 16 h later and their lipids were extracted, saponified, and analyzed by radio-HPLC. Most (≥ 90%) of the nonsaponifiable radioactivity was recovered as unmetabolized [³H]farnesol; however, about 6-8 % of the radioactivity in control retinas exhibited the chromatographic behavior of sterols, including cholesterol. Unlike the controls, the NB-598-treated retinas exhibited substantial accumulation of both [³H]squalene and squalene mass. Calculations indicate that most of the squalene mass was derived from metabolism of endogenous precursors, with an in vivo biosynthetic rate of 46 ± 17.5 pmol/retina/h. Retinas from eyes injected with all-trans [1-³H]geranylgeraniol yielded only the unmetabolized precursor in the nonsaponifiable extracts. These results suggest that farnesol can be 'activated' in vivo (presumably to the corresponding allylic pyrophosphate) in the retina and subsequently metabolized to sterols and sterol precursors.