The metabolism of fluperlapine, a neuroleptic dibenzazepine derivative with a N-methyl-piperazinyl substituent, was investigated in continuous cultures of rat and human cells which express various cytochrome P450-dependent monooxygenase activities. The differentiated rat hepatoma cells H4IIEC3/G- and their variants 2sFou and FGC-5 metabolized fluperlapine predominantly by N-oxygenation and only to a minor degree by N-demethylation or glucuronidation of primary phenolic products. Total fluperlapine metabolism in dedifferentiated rat hepatoma cells H5 and partially differentiated human hepatoma cells HepG2 was much smaller than in the differentiated rat hepatoma lines. This was primarily attributable to their low capacity for N-oxygenation. Human lung adenocarcinoma lines NCI-H322 and NCI-H358 formed only trace amounts of fluperlapine N-oxide. Pretreatment of 2sFou cells with benz(a)anthracene, phenobarbital or dexamethasone markedly increased the formation of N-demethylated and glucuronidated products but did not affect the rate of N-oxide formation. Guanethidine and cysteamine, inhibitors of flavin-dependent monooxygenase activity, reduced fluperlapine N-oxidation more strongly than aldrin epoxidation, a marker for cytochrome P450 activity. In contrast, n-octylamine inhibited aldrin epoxidation but was without effect on fluperlapine N-oxygenation. The results suggest that certain cells in continuous culture are capable of expressing flavin-dependent monooxygenase(s) in addition to cytochrome P450-containing monooxygenases. Such cells may offer useful systems for studying the oxidative metabolism of a broad spectrum of xenobiotics and analysing the importance of the two oxygenation reactions for the biological effects of their substrates.