Cytochrome P450 (CYP) is a membrane bound protein present in most tissues in the body. It is a member of a superfamily of proteins known as hemoproteins – those that contain a heme group that is active in the catalytic mechanism of these various proteins. Other members of this family in humans include hemoglobin, myoglobin, and endothelial nitric oxide synthetase.
The monooxygenase reaction is the most common reaction catalyzed by cytochrome P450 enzymes:
RH + O2 + NADPH + H+ ⇒ ROH + H2O + NADP+
During the enzymatic cycle while the substrate is in the active area of the enzyme, the heme iron is reduced from the ferric to the ferrous state. Molecular oxygen then temporarily binds at this site before being split, sending one oxygen atom to the R group of the substrate, and the other atom to bind with two hydrogen atoms making a water molecule.
This catalytic cycle is interrupted by the introduction of CO, which binds to the reduced ferrous iron instead of oxygen. The same binding of CO to the reduced iron in the hemoglobin molecule is responsible for the decreased oxygen carrying capacity seen in CO poisoning.
Countless chemicals are modified by the CYP system in the human body; specific to anesthesia there are a handful of these enzymes in the liver that are particularly important in the metabolism of anesthetic medications.
CYP 3A4 metabolizes (inactivates) acetaminophen, alfentanil, dexamethasone, fentanyl, lidocaine, methadone, midazolam, and sufentanil.
Propofol is partially metabolized by CYP 3A4, mostly by CYP 2B6.
Midazolam and propofol, grapefruit juice, antifungal drugs, protease inhibitors, “mycin” antibiotics, and some SSRIs inhibit 3A4, therefore prolonging the effect of drugs metabolized by this enzyme. Rifampin, rifabutin, tamoxifen, glucocorticoids, carbamazepine, barbiturates, and St. John’s Wort induce 3A4, increasing the metabolism of substrates.
CYP 2D6 converts codeine to morphine, as well as participating in the conversion of oxycodone and hydrocodone to their active metabolites, oxymorphone and hydromorphone. Patients on SSRIs may therefore not have as good pain control from these prodrugs as they will have less ability to convert to active metabolites.