OVERVIEW OF ENZYMES OF DRUG-METABOLISM

Most pharmacologically active molecules are lipophilic and remain un-i onized or only partially ionized at physiological pH Biotransformation means that a lipid-soluble xenobiotic or endobiotic compound is enzym atically transformed into polar, water-soluble, and excretable metabol ites. The major organ for drug biotransformation is the liver. The met abolic products often are less active than the parent drug or inactive . However, some biotransformation products (metabolites) may have enha nced activity or toxic effects. Thus biotransformation may include bot h ''detoxication'' and ''toxication'' processes. One of the major enzy me systems that determines the organism's capability of dealing with d rugs and chemicals is represented by the cytochrome P450 monooxygenase s. Studies in the last 15 years have provided evidence that cytochrome p450 occurs in many different forms or ''isozymes'' which differ in s pectral, chemical, and immunological properties and have different sub strate affinities. These isozymes also differ in their regulation and tissue distribution. Recombinant DNA studies indicate that between 40 and 60 structural genes code for different cytochrome P450 isozymes in a single organism. Other enzyme systems include dehydrogenases, oxida ses, esterases, reductases, and a number of conjugating enzyme systems including glucuronosyltransferases, sulfotransferases, glutathione S- transferases, etc. Environmental and genetic factors cause interindivi dual and intraindividual differences in drug metabolism and may alter the balance between toxification and detoxification reactions. Genetic polymorphisms lead to subpopulations of patients with decreased, abse nt, or even increased activities of certain reactions (e.g., CYP2D6, C YP2C19, N-acetyltransferase polymorphism). Environmental factors such as other drugs, steroids, dietary factors, alcohol, and cigarette smok e can induce or inhibit drug-metabolizing enzymes and cause intraindiv idual variation.