Cytochrome P450 enzyme system - Pharmacology

Cytochrome P450 enzyme system drug metabolism Pharmacology:

Definition and general overview

Cytochrome P450 enzyme system Also known as microsomal mixed-function oxidases (MFOs) and cyp450 monooxygenases and simply abbreviated as CYP, p450 or CYP450 enzymes system.

The CYPs are a superfamily of isozymes made of haem proteins that catalyzes most of the phase 1 oxidation-reduction processes of drugs metabolic reactions.

The name cytochrome P450 is derived from the spectral properties of this hemoprotein; In its reduced mean ferrous form, it bind with carbon monoxide to form a pink compound, which shows maximum absorption at 450 nm, that’s why they are named as p450,

In humans, over 50 individual P-450s have been identified but only about 12 are involved in the metabolism of most drugs. each member of which catalyzes the biotransformation of a unique spectrum of drugs, with some overlap in the substrate specificities and may act on the same substrates but at different rates. The only common feature of the many drugs metabolized by this pathway is lipid solubility.

The CYPs carry out drug metabolism and metabolize many structurally diverse chemicals. This is due to the multiple forms of CYPs and the capacity of a single CYP to metabolize many structurally distinct drugs. In addition, CYPs can metabolize a single compound at different positions on the molecule. the CYPs are considered unselective to bind and metabolize multiple substrates.

These enzymes are also responsible for all or part of the anabolism and catabolism of a number of endogenous compounds, such as steroid hormones, bile acids and prostaglandins.

Structure

Heme protein of the cytochrome p450 contains one atom of iron in a hydrocarbon cage that functions to bind oxygen during the reaction. Many other enzymes that use O2 as a substrate for their reactions contain heme.  E.g. hemoglobin. These enzymes catalyze an oxidation-reduction processes that requires CYP450, CYP450 reductase, NADPH (reducing agent), and O2.

 location

Many drug-metabolizing enzymes are located in the lipophilic endoplasmic reticulum membranes of the hepatic cells which has the greatest specific enzymatic activity, and other sites like GIT and Kidneys.

Nomenclature

CYPs are named with the root CYP followed by a number appointing the family, a letter denoting the subfamily, and another number naming the CYP form. Thus, CYP3A4 is family 3, subfamily A, and gene number 4.

Mechanism of drugs metabolism

These enzymes catalyze reactions that requires CYP450, CYP450 reductase, NADPH, and oxygen. First of all, in step 1, P450 containing ferric iron (Fe3+) combines with a molecule of drug (RH). And form a complex. Subsequently, in second step, NADPH donates an electron to the flavoprotein P450 reductase, and the flavoprotein is reduced from oxidized form which in turn reduces the iron to ferrous form (Fe2+), In third step, it combines with molecular oxygen and subsequently, combines with a proton and a second electron from flavoprotein P450 reductase to form an activated oxygen-P450-substrate (Fe2+OOH–RH) complex. This combines with another proton to yield water with the liberation of oxidized drug from the complex in the next step and regeneration of P450 enzyme.

In this oxidation-reduction process, two microsomal enzymes play a key role which are NADPH cytochrome P450 oxidoreductase and cytochrome P450.

In the overall reaction, the drug is oxidized, and oxygen is reduced to water. The mechanism involves a complex cycle but the overall net effect of the reaction is quite simple, the addition of one atom of oxygen to the drug to form a hydroxyl group, the other atom of oxygen being converted to water.

Cytochrome P-450 catalyzes several reactions, including aromatic and aliphatic hydroxylation reactions, dealkylation at nitrogen, sulfur, and oxygen atoms; heteroatom oxidations at nitrogen and sulfur atoms; reductions at nitrogen atoms; and ester and amide hydrolysis