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Role of Cytochrome P450 enzyme in toxin biotransformation.

The most important enzyme systems involved in phase I reactions are the cytochrome P-450
containing monooxygenases. Cytochrome P-450s, the carbon monoxidebinding pigments of
microsomes, are hemoproteins of the b cytochrome type. Unlike most cytochromes, they are
named not from the absorption maximum of the reduced form in the visible region but from
the unique wavelength of the absorption maximum of the carbon monoxide derivative of the
reduced form, namely, 450 nm.

The cytochrome P-450 system is actually a coupled enzyme system composed of two
enzymes: NADPH-cytochrome P-450 reductase, and a heme-containing enzyme, cytochrome
P-450. These enzymes are embedded in the phospholipid matrix of the endoplasmic
reticulum. The phospholipid phophatidylcholine is not involved directly in the electron
transfer but plays a crucial role in facilitating the interaction between these two enzymes. The
NADPH-cytochrome P-450 reductase has a preference for NADPH as its cofactor. It is a
flavoprotein capable of transferring one or two electrons to cytochrome P-450. In vertebrates,
the liver is the richest source of cytochrome P-450 and is most active in the
monooxygenations of xenobiotics. Cytochrome P-450 and other components of the
monooxygenase system dependent on it are also found in skin, nasal mucosa, lung, and GI
tract. In addition to these organs, its presence has been demonstrated in kidney, adrenal cortex
and medulla, placenta, testes, ovaries, fetal and embryonic liver, corpus luteum, aorta, blood
platelets, and the nervous system. In humans, cytochrome P-450 has been demonstrated in
fetal and adult liver, placenta, kidney, testes, fetal and adult adrenal gland, skin, blood
platelets, and lymphocytes. The mammalian liver cells contain more than one cytochrome P-
450. To date, at least 10 forms of cytochrome P-450 have been isolated from rat liver
microsomes. These differ in both the structure of the polypeptide chain and the specificity of
the reactions they catalyze (Sipes and Gandolfi, 1986). In addition, the types and amounts of
cytochrome P-450 vary with species, organ, age, health, sex, stress, and chemical exposure.
In contrast to cytochrome P-450, only one NADPHcytochrome P-450 reductase has been
isolated from a single source. Its concentration is usually one-tenth to onethirtieth that of
cytochrome P-450. Therefore, this enzyme must mediate the reduction of the many different
forms of cytochrome P-450.

The mechanism of cytochrome P-450 function is not clearly understood. The initial step
consists of the binding of the substrate to oxidized cytochrome P-450, followed by a one-
electron reduction catalyzed by NADPHcytochrome P-450 reductase to form a reduced
cytochrome- substrate complex. This complex can interact with CO to form the CO-complex,
which gives rise to the wellknown difference spectrum with a peak at 450 nm and also
inhibits monooxygenase activity.

The next several steps are less well understood. They involve an initial interaction with
molecular oxygen to form a ternary oxygenated complex. This ternary complex accepts a
second electron, resulting in the further formation of one or more poorly understood
complexes. One of these, however, is probably the equivalent of the peroxide anion
derivative of the substrate-bound hemoprotein. Under some conditions, this complex may
break down to yield hydrogen peroxide and the oxidized cytochromesubstrate complex.
Normally, however, one atom of molecular oxygen is transferred to the substrate and the
other is reduced to water, followed by dismutation reactions leading to the formation of the
oxygenated product, water, and the oxidized cytochrome.
Figure 1 : The mixed function oxidase system.

Oxidation Reactions Catalyzed by the Cytochrome P-450Containing Monooxygenases


1. Epoxidation and aromatic hydroxylation
2. Aliphatic hydroxylation
3. Aliphatic epoxidation
4. Dealkylation: O-, N-, and S-dealkylation
5. N-Oxidation
6. Oxidative deamination
7. S-Oxidation
8. P-Oxidation
9. Desulfuration and ester cleavage
10. Methylenedioxy (benzodioxole) ring cleavage
11. Oxidative dehalogenation

Sipes and Gandolfi (1986) have suggested the following criteria for the participation of
cytochrome
P-450 in a biotransformation reaction:
1. Enzymatic activity increased by induction
2. Enzymatic activity decreased by inhibitors
3. Substrates that produce characteristic difference spectra
4. Enzymatic activity reconstituted with individual purified components

References:
Takayuki.S(1993) Introduction to food toxicology, Academic Press Limited, London, First
edition, 147pp.

Deshpande .S.S(2002) Handbook of food toxicology, Marcel Dekker, New York, First
edition, 880pp.

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