Cytochrome P450 - arranged by substrate type

RH (substrate) + O2 + NADPH + H+ = ROH (product) + H2O + NADP+

The end results of this reaction can be (N-)hydroxylation, epoxidation, heteroatom (N-, S-) oxygenation, heteroatom (N-, S-, O-) dealkylation, ester cleavage, isomerization, dehydrogenation, replacement by oxygen or even reduction under anaerobic conditions.

The metabolites produced from these reactions can either be mere intermediates which have relatively little reactivity towards cellular sysytems and are readily conjugated, or, they can be disruptive to cellular systems. Indeed, inert compounds need to be prepared for conjugation and thus the formation of potentially reactive metabolites is in most cases unavoidable.

There are 57 human CYPs (in 18 families and 42 subfamilies), mostly concentrated in the endoplasmic reticulum of liver cells although many tissues have them to some extent (Nelson DR et al, 2004). CYPs are grouped into 14 families according to their sequence similarity. Generally, enzymes in the same family share 40% sequence similarity and 55% within a subfamily. Nomenclature of P450s is as follows. CYP (to represent cytochrome P450 superfamily), followed by an arabic number for the family, a capital letter for the subfamily and finally a second arabic number to denote the isoenzyme. An example is CYP1A1 which is the first enzyme in subfamily A of cytochrome P450 family 1.

The majority of the enzymes are present in the CYP1-4 families. CYP1-3 are primarily concerned with xenobiotic biotransformation whereas the other CYPs deal primarily with endogenous compounds. The CYP section is structured by the typical substrate they act upon. Of the 57 human CYPs, 7 encode mitochondrial enzymes, all involved in sterol biosynthesis. Of the remaining 50 microsomal enzymes, 20 act upon endogenous compounds, 15 on xenobiotics and 15 are the so-called "orphan enzymes" with no substrate identified.

The P450 catalytic cycle (picture) shows the steps involved when a substrate binds to the enzyme.

(1) The normal state of a P450 with the iron in its ferric [Fe3+] state.

(2) The substrate binds to the enzyme.

(3) The enzyme is reduced to the ferrous [Fe2+] state by the addition of an electron from NADPH cytochrome P450 reductase. The bound substrate facilitates this process.

(4,5) Molecular oxygen binds and forms an Fe2+OOH complex with the addition of a proton and a second donation of an electron from either NADPH cytochrome P450 reductase or cytochrome b5. A second proton cleaves the Fe2+OOH complex to form water.

(6) An unstable [FeO]3+ complex donates its oxygen to the substrate (7). The oxidised substrate is released and the enzyme returns to its initial state (1).