The assessment of flavin-containing monooxygenase activity in intact animals.

Abstract

A large number of drug metabolising enzymes with different substrate specificities and induction and inhibition characteristics have been described, suggesting that specific test drugs, i.e. probes, should be used for assessing the activity of distinct metabolising enzymes. The flavin-containing monooxygenase (FMO) and cytochrome P-450 (P-450) are the two main microsomal enzyme systems involved in the oxidation of xenobiotics. FMO is present in liver and other tissues of most vertebrates. It catalyses the oxidation of a wide range of xenobiotics, especially soft nucleophiles bearing nitrogen and sulphur centres. There is substantial information on both in vitro and in vivo probes for cytochrome P-450. For example antipyrine has been widely used for assessing the activity of P-450 in vivo by utilising pharmacokinetic parameters as indices of enzyme activity. In more recent years, isozyme specific probes have also been developed for some of the P-450s. Whereas a number of substrates are available for measuring FMO activity in vitro (e.g. N,N-dimethylaniline), probes for assessing FMO activity in vivo are limited. In this review a background to the use of in vitro and in vivo probes for assessing the activity of FMO is presented, and approaches and criteria for development of potential pharmacokinetic probes for FMO are described. Preliminary data on the development of ethyl methyl sulphide (EMS) and trimethylamine (TMA) as potential pharmacokinetic probes for assessing FMO activity in rats are discussed in detail. Clinical implications of modulation of FMO activity are discussed, and arguments presented as to why the development of FMO probes for use in man will be useful additions to the range of other compounds available for assessment of liver metabolic function.