P2A33 - Induction of hepatic phase I and phase II metabolizing enzymes in the female fischer 344 rat by cyclicsiloxanes

Abstract

Dextran sulfate sodium (DSS) induced experimental colitis presents a histologic resemblance to human ulcerative colitis (UC). Altered cytochrome P450s (CYPs) have been reported in this model and patients with UC. In this study, six CYPs activities were quantitatively determined in microsomes of liver (RLMs), kidney (RRMs) and intestine (RIMs) from rats with colitis at acute (5% DSS for 7 days, UCA) and remission (7-day DSS treatment followed by 7-day cessation, UCR) phases and compared with normal rats. Generally, CYPs activities varied with isoform, organ, and disease status. Hepatic CYP1A2, 2B1, 2C6/11, 2E1 and 3A1/2 activities were reduced by acute colitis and completely or partially restored after DSS was halted. Although DSS treatment decreased the Vmax of renal CYP2C6/11 and increased that of CYP2D2, their CLint, in vitro were comparable among normal, acute and remission stages. DSS treatment changed the kinetics of CYP3A1/2-mediated nifedipine metabolism in RRMs from biphasic to classical kinetics. Notably, CYP2D2 activity was elevated in liver and kidney in acute UC, while enhanced in liver and decreased in kidney in remission. In intestine, CYP3A1/2 activity was increased in UCA and further enhanced after DSS withdrawal. These findings highlight the necessity of quantifying enzyme activity for precision drug therapy.