Cytochrome P40 (CYP)

Cytochrome P40 enzymes are a superfamily of mono-oxygenases that are found in all
kingdoms of life, and which show extraordinary diversity in their reaction chemistry. In
mammals, these enzymes are found primarily in the membranes of the endoplasmic reticulum
(microsomes) within liver cells (hepatocytes), as well as many other cell types. These enzymes
use haem iron to oxidise molecules, often making them more water-soluble for clearance. They
achieve this by either adding or unmasking a polar group.
The term P450 is derived from the spectrophotometric peak at the wavelength of the
absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed
with carbon monoxide
These
enzymes
are
identified
in
all domains of
lifeanimals, plants, fungi, protists, bacteria, and even in viruses. However, the enzymes have not
been found in E. coli. There are thousands in nature but there are only 57 human genes coding
for P450 enzymes (The Human Genome Project). These enzymes are significant as they:
Oxidize xenobiotics compounds and are important for detoxification of foreign
substances
Control the level of endogenous compounds, such as hormone synthesis and
breakdown, cholesterol synthesis and vitamin D metabolism

Involved in vascular autoregulation, especially in the brain, and are vital to the formation
of cholesterol, steroids and arachidonic acid metabolites
Cytochrome P40 in Mammals
Cytochrome P40 are vital in the life of humans regarding xenobiotics. 56% of 315 drugs
were primarily cleared by CYP (Bertz and Granneman, 1997). CYP1, 2, 3 families, are
responsible for the biotransformation of 7080% of all drugs in clinical use ( Zanger , 2012). In
the membranes of the endoplasmic reticulum (microsomes) within hepatocytes, there is a high
concentration of these, but these enzymes are also found throughout the body, where they
often have specialized roles.
In adrenal gland, they are found in mitochondria as well as in the ER.Hydroxylases present
in gland are involved in cholesterol and steroid hormone biosynthesis. Mitochondrial CYP, unlike
the microsomal system, uses an NADPH-linked flavoprotein called adrenodoxin reductase, and
a nonheme iron-sulfur protein, adrenodoxin .They use heme iron to oxidize water soluble
body's strategy to dispose of potentially harmful substances
Cytochrome P450 Reaction
The enzymes catalyze a variety of reactions including:
Epoxidation
N-dealkylation
O-dealkylation
S-oxidation
hydroxylation
The reaction proceeds in this way: R-H + O2 + NADPH + H+ R-OH + H2O + NADP +

CYP Isoform
An isoform is an CYP enzyme variant that derives from one particular gene. They are
classified according to the similarities of their amino acid sequences. The most significant are
CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP3A5
In naming, for example: CYP3A4
CYP = cytochrome 450
Family (3) = exhibit > 40% AA sequence identity
Subfamily (A) = exhibit > 55% sequence identity
Individual (4)
Gene for CYP3A4 is CYP3A4
Expression of each CYP is influenced by a unique combination of mechanisms and factors
genetic polymorphisms
induction
regulation by cytokines, hormones
disease states
sex
age
These isoforms may explain the variations in drug responses among many patients. Variants
with low catalytic activitywould result to slower metabolism of substrate and thus, prolonged
drug action and accumulation of drug in body.

Another example is nicotine with CYP2A6 conitine

3 alleles: 1 wild type and 2 null types
*Null type impaired metabolism of nicotine smoke less because blood and brain nicotine
cnxns elevated longer protected against becoming tobacco-dependent smokers
These enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug
interactions that can cause unanticipated adverse reactions or therapeutic failures
Inducible Isoforms
Most isoforms are inducible. This happen through:
Increased transcription of mRNA

Stabilization of mRNA or protein itself

Increase translation
Example: Administration of phenobarbital hypertrophy of ER 3-4x increase in CYP in 4-5
days