The main reaction involved in phase 1 metabolism is hydroxylation, catalyzed by a family of monoxygenase enzymes known as cytochromes P450. There are at least 57 genes encoding cytochrome P450 in the human genome. Cytochrome P450 is a heme enzyme. It is so named because it was originally discovered when it was noted that preparations of microsomes (fragments of the endoplasmic reticulum) that had been chemically reduced and then exposed to carbon monoxide had an absorption peak at 450 nm.

At least half of the common drugs that we ingest are metabolized by isoforms of cytochrome P450. They also act on steroid hormones, carcinogens, and pollutants. In addition, cytochromes P450 are important in the metabolism of a number of physiological compounds—for example, the synthesis of steroid hormones (see Chapter 26) and the conversion of vitamin D to its active metabolite, calcitriol (see Chapter 44).

The overall reaction catalyzed by cytochrome P450 is:

RH + O2 + NADPH + H+ → R-OH + H2O + NADP

. NADPH-cytochrome P450 reductase catalyzes the transfer of electrons from NADPH to cytochrome P450. Reduced cytochrome P450 catalyzes the reductive activation of molecular oxygen, one atom of which becomes the hydroxyl group in the substrate and the other is reduced to water. Cytochrome b5 , another hemoprotein found in the membranes of the smooth endoplasmic reticulum, may be involved as an electron donor in some cases.

Isoforms of Cytochrome P450 Form a Superfamily of Heme-Containing Enzymes There is a systematic nomenclature for the cytochromes P450 and their genes, based on their amino acid sequence homology. The root CYP denotes a cytochrome P450. This is followed by number designating the family; cytochromes P450 are included in the same family if they exhibit 40% or more amino acid sequence identity. This is followed by a capital letter indicating the subfamily; P450s are in the same subfamily if they exhibit more than 55% sequence identity. Theindividual P450s are then assigned numbers in their sub family. Thus, CYP1A1 denotes a cytochrome P450 that is a member of family 1 and subfamily A and is the first individual member of that subfamily. The nomenclature for the genes encoding cytochromes P450 is the same, except that italics are used; thus, the gene encoding CYP1A1 is CYP1A1.

The major families of cytochromes P450 involved in drug metabolism are CYP1 (with 3 subfamilies), CYP2 (13 subfamilies), and CYP3 (1 subfamily). The various cytochromes P450 have overlapping substrate specificities, so that a very broad range of xenobiotics can be metabolized by one or other of the enzymes.

Cytochromes P450 are present in greatest amount in liver cells and enterocytes. In liver and most other tissues, they are present mainly in the membranes of the smooth endo plasmic reticulum, which constitute part of the microsomal fraction when tissue is subjected to subcellular fractionation. In hepatic microsomes, cytochromes P450 can comprise as much as 20% of the total protein. In the adrenal gland, where they are involved in cholesterol and steroid hormone biosynthesis, they are found in mitochondria as well as in the endo plasmic reticulum.

Overlapping Specificity of Cytochromes P450 Explains Interactions Between Drugs and Between Drugs and Nutrients

Most isoforms of cytochrome P450 are inducible. For instance, the administration of phenobarbital or other drugs causes hypertrophy of the smooth endoplasmic reticulum and a three- to fourfold increase in the amount of cytochrome P450 within a few days. In most cases this involves increased transcription to mRNA. However, in some cases, induction involves stabilization of mRNA or the enzyme protein itself, or increased translation of existing mRNA.

Induction of cytochrome P450 underlies drug interactions, when the effects of one drug are altered by administration of another. For example, the anticoagulant warfarin is metabolized by CYP2C9, which is induced by phenobarbital. Induction of CYP2C9 will increase the metabolism of warfarin, so reducing its efficacy, so that the dose must be increased. CYP2E1 catabolizes the metabolism of some widely used sol vents and compounds found in tobacco smoke, many of which are procarcinogens; it is induced by ethanol, so increasing the risk of carcinogenicity.

Naturally occurring compounds in foods may also affect cytochrome P450. Grapefruit contains a variety of furanocoumarins, which inhibit cytochrome P450 and so affect the metabolism of many drugs. Some drugs are activated by cytochrome P450, so that grapefruit will reduce their activity; others are inactivated by cytochrome P450, so that grapefruit increases their activity. Drugs that are affected include statins, omeprazole, antihistamines, and benzodiazepine antidepressants.

Polymorphism of cytochromes P450 may explain much of the variation in drug responses by different patients; variants with low catalytic activity will lead to slower metabolism of the substrate, and hence prolonged drug action. CYP2A6 is involved in the metabolism of nicotine to conitine. Three CYP2A6alleles have been identified: a wild type and two inactive alleles. Individuals with the null alleles, who have impaired metabolism of nicotine, are apparently protected against becoming tobacco-dependent smokers. These individuals

smoke less, presumably because their blood and brain concentrations of nicotine remain elevated longer than those of individuals with the wild-type allele. It has been speculated that inhibiting CYP2A6 may provide a novel way to help smoking cessation.

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المزيد

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