cytochrome P-450 system
cytochrome P-450 system
The steady increase in the number and variety of pharmaceutical agents available for the treatment of infections, degenerative and malignant conditions, mental disorders, and other diseases has led to polypharmacy, with attendant risks of undesirable drug interactions. Disturbances in the function of the cytochrome P-450 system are increasingly recognized as important causes of such interactions. When a drug increases the formation of a P-450 enzyme, other drugs metabolized by that enzyme are eliminated more rapidly and may fail to produce the desired therapeutic effects. In contrast, a drug that inhibits P-450 enzyme activity can retard the metabolism of substrate drugs, with resultant increases in serum and tissue levels and in drug effects, including side-effects. Inhibition usually involves competition between drugs for the same binding site on an enzyme molecule. Reversible inhibition is the most common mechanism of drug interactions involving the P-450 system. In general, drugs compete for a specific P-450 isoenzyme. Examples of agents that cause interactions through reversible inhibition are fluoroquinolone antibiotics, cimetidine, ketoconazole, and protease inhibitors used in the treatment of AIDS. The most abundant human cytochrome P-450 enzyme is CYP3A4, which is involved in the metabolism of about 50% of medicines in current use. Ethnic differences in the expression of CYP2D6 explain why whites are more likely than blacks and Asians to experience toxicity from accumulation and excessive serum levels of drugs metabolized by this enzyme, such as tricyclic antidepressants, SSRIs, antipsychotics, and beta-blockers.