UK-157147

UK-157147 is a substrate for UDP-glucuronosyltransferases (UGT1A1) with a Km value of 105 μM.

Signaling Pathways >> Others >> Others

Research Areas >> Metabolic Disease

Km: 105 μM (UGT1A1)[1]

Glucuronidation is an important pathway for human drug metabolism. Four cloned and expressed human UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B15) are used to screen a series of three potential drug substrates differing only in position of the phenol moiety. The para phenol UK-157147 (UK-157,147) is found to be a substrate for UGT1A1 with a Km value of 105 μM[1].

UGT assays are performed. Assays are incubated in 100 mM Tris/maleate buffer (pH 7.4) containing 5 mM MgCl2, typically 500 μM substrate, and 350 to 500 μg of cellular sonicate in a total volume of 100 μL. Screening assays are incubated for 60 min at 37°C at two concentrations of UDPGA: 50 μM and 2 mM (containing 0.1 μCi [14C]UDPGA). UDPGA (50 μM) assays allow higher levels of radiolabel incorporation into the glucuronide, which enhances assay sensitivity making this a useful tool for screening. Kinetic determinations are performed at 2 mM UDPGA or higher. The compounds screened are UK-157147 (UK-157,147), UK-156,037, and UK-157,261. Each batch of screening assays is accompanied by positive controls for the cell lines: UGT1A9, 500 μM propofol; UGT1A6, 500 μM 1-naphthol; UGT1A1, 250 μM 17α-ethinylestradiol; and UGT2B15, 500 μM 8-hydroxyquinoline. The unknown compounds are also assayed with human liver microsomes to establish a retention time for the radiolabeled conjugate on the radiochemical HPLC system[1].

[1]. Ethell BT, et al. Use of cloned and expressed human UDP-glucuronosyltransferases for the assessment of human drug conjugation and identification of potential drug interactions. Drug Metab Dispos. 2001 Jan;29(1):48-53.

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