METABOLIC-ACTIVATION OF TOXINS - TISSUE-SPECIFIC EXPRESSION AND METABOLISM IN TARGET ORGANS

Cytochrome P450 (CYP) enzymes catalyze the generation of reactive spec ies capable of binding with cellular macromolecules, leading to acute and delayed toxicity. Since individual CYP forms differ markedly in th eir substrate preferences and regulation, the expression profiles of C YP in various cell types are important determinants in tissue-specific toxicity. The highest concentrations of most forms of CYP are found i n liver, but they are also present in many extrahepatic organs. Liver is also a target organ in which CYP-mediated activation and toxic outc ome have been most convincingly linked. Prime examples are paracetamol -induced hepatotoxicity and aflatoxin B-1-associated hepatic cancer. I n contrast to liver, most extrahepatic tissues are composed of multipl e cell types, which make experimental approaches difficult. Also the l ow abundance of individual forms is a challenge in the study of extrah epatic CYP-related toxicity. Recent years have witnessed the emergence of molecular biological techniques, e.g.. reverse transcriptase-polym erase chain reactions, which facilitate the study of low abundant CYP forms in human tissues. Nevertheless in the end we need definite infor mation on the expression of activity, and for this purpose enzyme-spec ific substrates, reactions, and inhibitors and other methods to detect proteins and associated activities are needed. in humans, it is impor tant to measure activities of specific enzymes in vivo. For this purpo se, two approaches are currently available. Metabolism and/or eliminat ion of enzyme-specific drugs can be employed. In cases in which geneti c background determines the presence or absence of a specific enzyme, phenotyping and genotyping tests can be devised, e.g., for CYP2D6 (deb risoquine hydroxylation) polymorphism.