Hepatic Microsomal Drug Metabolizing Systems

c. An important oxidizing enzyme system is the cytochrome P-450 system (CYP 450). It is composed of at least 30 isoenzymes.

The more important ones are;

• CYP1A2 (metabolizes theophylline, caffeine; acetaminophen),

• 2D6 {metabolizes tricyclic antidepressants, opioids, B-blockers, phenothiazines, 1-B & 1-C antiarrhythmics),

• 3A4 (metabolizes cyclosporine, erythromycin, calcium channel blockers, lovastatin, triazolam, tamoxifen, quinidine and many others),

• 2C group (phenytoin, S-warfarin, imipramine, tolbutamide).

These enzyme systems may be stimulated (enzyme induction) or inhibited (enzyme inhibition). Cytochrome requires an electron obtained from NADPH plus oxygen to be function. Cytochrome P-450 goes from the reduced to oxidized state by change in valence of an iron molecule.

Cimetidine binds to the iron molecule, preventing the change in valence and inhibiting the action of cytochrome P-450. Thus, cimetidine affects several of the P450 isozymes.

The oxidation enzymes are occasionally called the "mixed function oxidases" (MFO) because of the variety of metabolic processes affected (e.g., hydroxylation, demethylation, etc). Certain ethnic groups or individuals possess genes that cause alterations on aminoacid sequences of enzymes or receptor sites (sometimes termed polymorphisms).

Clinical observations of inherited differences in drug effects have given rise to the field of pharmacogenetics.

d. Many phase I enzymes, particularly oxidizing enzymes, are "inducible" (i.e., certain compounds will increase enzyme activity). A number of enzymes are can also be inhibited. Phase II enzymes generally are not (as always, in pharmacology, there are exceptions) capable of being induced by drugs or other chemicals. These terms are further discussed under drug interactions.

e. Glucuronidation

Glucuronic acid is a large endogenous water soluble compound that is attached (by glucuronyl transferase) to many phenols, alcohols, amines, hydroxyl compounds, & carboxylic acids during phase II metabolism. These reactive groups (phenols, alcohols, etc.) are often produced by phase I metabolism. Glucuronides are generally inactive (exception, morphine-6-glucuronide), are not affected by enzyme induction or inhibition, and are rapidly secreted into the urine or bile. Glucuronyl transferase is deficient in neonates & premature infants (hence drugs largely glucuronidated [e.g., chloramphenicol] quickly reach toxic levels in neonates).

Category: Pharmacology Notes