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THE OLIVACINE DERIVATIVE S 16020 (9-HYDROXY-5,6-DIMETHYL-N-[2-(DIMETHYLAMINO)ETHYL)-6H-PYRIDO(4,3-B)-CARBAZOLE-1-CARBOXAMIDE) INDUCES CYP1A AND ITS OWN METABOLISM IN HUMAN HEPATOCYTES IN PRIMARY CULTURE

Institut National de la Santé et de la Recherche Médicale U128 (L.P.-G., J.-M.F, P.M.), and Service de Chirurgie C, Centre Hospitalier Universitaire (J.-M.F.), Montpellier, France; Servier Research and Development Ltd., Fulmer, United Kingdom (R.J.W., N.E., G.S.); and IRI Servier, Courbevoie, France (C.L.)

The olivacine derivative 9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-b)-carbazole-1-carboxamide (S 16020) exhibits a potent antitumor activity. However, when administered in cancer patients, its blood clearance increases after repeated administrations, whereas the volume of distribution remains constant, suggesting that the drug is able to induce its own metabolism. The aim of this work was to identify the enzymes involved in S 16020 metabolism and determine whether this molecule is an enzyme inducer in human hepatocytes in primary cultures. Among a battery of cDNA-expressed cytochromes P450 (P450s) and flavin monooxygenase (FMO), only CYP1A1, CYP1A2, and FMO3 were able to generate detectable amounts of metabolites of S 16020. In primary hepatocytes, S 16020 behaved as a CYP1A inducer, producing an increase in CYP1A2 protein, acetanilide 4-hydroxylation, ethoxyresorufin O-deethylation, and chlorzoxazone 6-hydroxylation to an extent similar to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical CYP1A inducer. The levels of other P450 proteins, including CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, and related activities were not affected by S 16020. In primary hepatocytes, pretreatment of cells with S 16020 or TCDD produced a significant and similar increase of S 16020 metabolism, consistent with the previous indications on the role of CYP1As. We conclude that CYP1As and FMO3 are the major phase I enzymes involved in the metabolism of S 16020 and that this molecule is a potent hydrocarbon-like inducer able to stimulate its own metabolism in primary human hepatocytes and liver.

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