Kinetic studies of the inhibition of a human liver 3α-hydroxysteroid/dihydrodiol dehydrogenase isozyme by bile acids and anti-inflammatory drugs

Article abstract of DOI:10.1248/bpb.18.9

We have investigated the steady-state kinetics for a cytosolic 3α-hydroxysteroid/dihydrodiol dehydrogenase isozyme of human liver and its inhibition by several bile acids and anti-inflammatory drugs such as indomethacin, flufemanic acid and naproxen. Initial velocity and product inhibition studies performed in the NADP⁺-linked (S)-1-indanol oxidation at pH 7.4 were consistent with a sequential ordered mechanism in which NADP⁺ binds first and leaves last. The bile acids and drugs, competitive inhibitors with respect to the alcohol substrate, exhibited uncompetitive inhibition with respect to the coenzyme, with K(i) values less than 1 μM, whereas indomethacin exhibited noncompetitive inhibition (K(i) < 24 μM). The kinetics of the inhibition by a mixture of the two inhibitors suggests that bile acids and drugs, except indomethacin, bind to overlapping sites at the active center of the enzyme-coenzyme binary complex.

Full text of DOI:10.1248/bpb.18.9

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NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service