P450 CYTOCHROME MECHANISM:

P450 Cytochrome’s mechanism of action of enzyme

activity can be explained in a series of simple
chemical steps:

 Substrate trapping begins to cytochrome ferric

(Fe3 +).

 An electron is transferred to the Fe atom,

moving it to its ferrous state (Fe2 +), this
transfer is often carried out by protein
cytochrome b5.
 The ferrous form binds to a molecule of
O2.

 A second reduction is done by adding an

electron and a proton.

 This intermediate loses a water molecule

leaving a complex (FeO) 3 + that directly
oxidizes the substrate.
 The P450 was found in the membrane of the endoplasmic reticulum
(a cellular organelle of most animal cells).

 The electrons involved in the oxidation of substrates in the hands of

cytochrome P450 may come from or NADPH (nicotinamide adenine
dinucleotide phosphate) from the cytoplasm or cytochrome b5 which
is located in the membrane .
P450 IN HUMANS :
 Some CYPs metabolize only one (or a very few) substrates, such as
CYP19 (aromatase), while others may metabolize multiple substrates.

 Both of these characteristics account for their central importance in

medicine.

 play important roles in hormone synthesis and breakdown

(including estrogen and testosterone synthesis and metabolism),
cholesterol synthesis, and vitamin D metabolism.

 also function to metabolize potentially toxic compounds, including

drugs and products of endogenous metabolism such as bilirubin,
principally in the liver.
 The Human
Genome
Project has
identified 57
human genes
coding for the
various
cytochrome
P450 enzymes
 DRUG METABOLISM

 CYPs are the major

enzymes involved in drug
metabolism, accounting
for ~75% of the total
metabolism.
 undergo deactivation by
CYPs, either directly or by
facilitated excretion
 substances are also
bioactivated by CYPs to
form their active
compounds.
 DRUG INTERACTION

 drugs may increase or decrease the activity of

various CYP isozymes.
 changes in CYP enzyme activity may affect
the metabolism and clearance of various
drugs.

 A classical example includes anti-epileptic

drugs.
Phenytoin, for example, induces CYP1A2,
CYP2C9, CYP2C19, and CYP3A4.
 INTERACTION OF OTHER
SUBSTANCES:

 Naturally occurring compounds may also induce or inhibit CYP

activity.

 For example,
bioactive compounds found in grapefruit juice and some other fruit
juices, including bergamottin, dihydroxybergamottin, and paradisin-A,
have been found to inhibit CYP3A4-mediated metabolism of certain
medications, leading to increased boavailability.

 Because of this risk, avoiding grapefruit juice and fresh grapefruits

entirely while on drugs is usually advised.
 OTHER EXAMPLES:

 Tobacco smoking induces CYP1A2

(example CYP1A2 substrates are
clozapine, olanzapine, and fluvoxamine)

 At relatively high concentrations,

starfruit juice has also been shown to
inhibit CYP2A6 and other CYPs.

 Watercress is also a known inhibitor of

the Cytochrome P450 CYP2E1, which
may result in altered drug metabolism
for individuals on certain medications
(ex., chlorzoxazone).