Study of in vitro glucuronidation of hydroxyquinolines with bovine liver microsomes

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Abstract
Glucuronidation of drugs by UDP‐glucuronosyltransferase (UGT) is a major phase II conjugation reaction. Defects in UGT are associated with Crigler–Najjar syndrome and Gilbert's syndrome with severe hyperbilirubinaemias and jaundice. We analysed the reactivities of some hydroxyquinoline derivatives, which are naturally produced from quinoline by cytochrome P450. The analyses were carried out using a microassay system for UGT activity in bovine liver microsomes in the range 0.5–100 pmol/assay with the highly sensitive radio‐image analyser Fuji BAS2500 (Fujifilm, Tokyo, Japan). 3‐Hydroxylquinoline is a good substrate for glucuronidation, and the relative Kcat values were 3.1‐fold higher than the values for p‐nitrophenol. 5,6‐Dihydroquinoline‐5,6‐trans‐diol gave a similar Km value to that of 3‐hydroxyquinoline, but the Vmax value was approximately 1/15 of that of p‐nitrophenol and showed weak reactivity. Quinoline N‐oxide gave a low Vmax value and showed marginal activity. The Kcat values of 6‐hydroxyquinoline and 5‐hydroxyquinoline were 2.1‐ and 1.2‐fold higher than that of p‐nitrophenol, respectively. Fluoroquinoline (FQ) derivatives, such as 3FQ, 7,8diFQ and 6,7,8triFQ, did not show any substrate activities. These results suggest that there are therapeutic problems in administration of some quinoline drugs to patients with jaundice.