Differential metabolism of dihomo-γ-linolenic acid and arachidonic acid by cyclo-oxygenase-1 and cyclo-oxygenase-2: Implications for cellular synthesis of prostaglandin E₁ and prostaglandin E₂

Prostaglandin (PG) E₁ has been shown to possess anti-inflammatory properties and to modulate vascular reactivity. These activities are sometimes distinct from those of PGE₂, suggesting that endogenously produced PGE₁ may have some beneficial therapeutic effects compared with PGE₂. Increasing the endogenous formation of PGE₁ requires optimization of two separate processes, namely, enrichment of cellular lipids with dihomo-γ-linolenic acid (20:3 n-6; DGLA) and effective cyclo-oxygenase-dependent oxygenation of substrate DGLA relative to arachidonic acid (AA; 20:4 n-6). DGLA and AA had similar affinities (K_m values) and maximal reaction rates (V_max) for cyclo-oxygenase-2 (COX-2), whereas AA was metabolized preferentially by cyclo-oxygenase-1 (COX-1). To overcome the kinetic preference of COX-1 for AA, CP-24879, a mixed Δ⁵/Δ⁶ desaturase inhibitor, was used to enhance preferential accumulation of DGLA over AA in cells cultured in the presence of precursor γ-linolenic acid (18:3 n-6). This protocol was tested in two cell lines and both yielded a DGLA/AA ratio of approx. 2.8 in the total cellular lipids. From the enzyme kinetic data, it was calculated that this ratio should offset the preference of COX-1 for AA over DGLA. PGE₁ synthesis in the DGLA-enriched cells was increased concurrent with a decline in PGE₂ formation. Nevertheless, PGE₁ synthesis was still substantially lower than that of PGE₂. It appears that employing a dietary or a combined dietary/pharmacological paradigm to augment the cellular ratio of DGLA/AA is not an effective route to enhance endogenous synthesis of PGE₁ over PGE₂, at least in cells/tissues where COX-1 predominates over COX-2.