XENOBIOTIC METABOLISM IN BRAIN

Recent hypothesis suggesting a role for environmental toxins in the pa thogenesis of neurodegenerative disorders has stimulated interest in r esearch on xenobiotic metabolizing capability of the brain. In additio n to possible irreversible loss of neurons through bioactivation in si tu in the nervous tissue, the metabolism of psychoactive drugs in the target tissue can lead to local pharmacological modulation at the site of action. The major drug metabolizing enzymes, cytochromes P-450 (P4 50) and flavin-containing monooxygenase (FMO) have been detected in ro dent brain and human brain tissue obtained at autopsy. The brain micro somal and mitochondrial P450 systems are capable of metabolizing a var iety of xenobiotics, while the brain FMO efficiently metabolizes a var iety of psychoactive drugs to their respective N-oxides, Immunocytoche mical studies have revealed the regional heterogeneity in the distribu tion of multiple forms of P450 in the brain and the co-localization of P450 and FMO predominantly in the neuronal cells, Although the brain P450 and FMO share many common features with similar enzymes present i n other tissues such as liver and lung, there are some distinctive dif ferences. It is evident from the studies carried out so far that the b rain can metabolize a variety of lipophilic xenobiotics that enter by way of the blood stream.