An Approach to the Elucidation of Metabolic Breakdown Products of the Luteinizing Hormone-Releasing Hormone

Article abstract of DOI:10.1021/jm00138a009

Metabolic breakdown of the luteinizing hormone-releasing hormone (LH-RH) could lead to the following fragments containing pyroglutamic acid: pyroglutamic acid (1), pGlu-His (2), pGlu-His-Trp (3), pGlu-His-Trp-Ser (4), etc., and finally pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly (10).We have synthesized fragments 2-10 and successfully separated all ten metabolites and LH-RH by high-performance liquid chromatography (HPLC) with μBondapak C₁₈ column.In a test of viability of the method, cochromatography of fragments 1-10 and LH-RH with the products of chymotryptic digestion of tritiated LH-RH showed radioactive peaks corresponding to the expected products, fragments 3 and 5.Analysis of the products of incubation of a rat kidney homogenate supernatant with LH-RH showed fragments 1-4 and LH-RH.The finding of breakdown at position 4 uncovers a new site of LH-RH breakdown and points the way to the design of potential LH-RH antagonists and agonists where the 4 position would be substituted with unnatural amino acids to prevent breakdown.