Exten Industries (fka BB: EXTI)

[Patricia_1]

Cytochrome P450 family of liver enzymes

By: buckitz
04 Mar 2004, 01:41 PM EST
Msg. 24249 of 24288
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Afternoon all.

Here is an excerpt from a medical journal summarizing, in some detail the Cytochrome P450 family of liver enzymes. I have also included a direct link to the full article I pulled it from, in case you are interested. First, a brief VERY GENERAL description of how DDI's are important.

If you can understand the basics of this...understanding the importance of drug-drug interactions becomes more clear. Very few people enter a physician's office who are not on several medications. Most medications are processed through the liver (some in the kidney). By processed I mean detoxify, because most drugs are "toxins" in their own way.

If you give someone drug "A" that works well for the patient and doesn't raise liver enzymes...no problem. If you add drug "B", then several things can happen.
1. Nothing - no interaction because they are metabolized by a different liver enzyme family.
2. Drug "B" binds better to the same enzyme drug "A" does, thus increasing the levels of drug "A" in the body----possibly causing harmful effects.
3. Drug "A" and "B" together, may bind the same, or different enzymes and are too much for the liver, causing direct liver toxicity.

There are other possiblities, but this may be a simple way to see the point.

Now, when making a new drug, the benefits must far outweigh the risks...so DDI are very important, but often hard to know much about until too far into development. It is impossible to test a new drug against every known prescribed or over-the-counter medicine. This technology would at least allow a way to quickly test the new product against drugs using the major families of Cytochrome p450 enzyme, and assess for DDI.

Please understand that this is a complex subject that I tried to simplify for those of you who want to understand a little better. Unfortunately, my schedule doesn't allow for me to respond, or check this site much. I do hope this is of some help, however. Here is the information.....

Cheers!

The cytochrome P450 superfamily
Hepatic metabolism is served by a superfamily of oxygenases known as the cytochrome P450s. The purpose of these enzymes is to add a functional group to a drug, an environmental chemical or an endogenous molecule and, in so doing, increase either its polarity and excretion from the body or its interaction with similar enzymes. The most distinguishing characteristic of the cytochrome P450 family is its great diversity; members have a broad and overlapping substrate specificity and an ability to interact with almost any chemical species. The superfamily, referred to as the CYP enzymes, is subdivided according to the degree of homology in amino acid sequences. CYP enzymes possessing more than 40% homology are grouped together into families, which are designated by an Arabic numeral (e.g., the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (e.g., CYP2C and CYP2D subfamilies); members of each subfamily have more than 55% homology with one another. Finally, individual members are given an additional number (e.g., CYP3A4) to identify a specific enzyme pathway. Over 70 CYP families have been identified to date, of which 14 are known to occur in all mammals.11 Of the 26 mammalian subfamilies, the CYP2C, CYP2D and CYP3A subfamilies are involved in the metabolism of most clinically relevant drugs. Important substrates, inducers and inhibitors of the major CYP enzymes are listed in Table 1.

The CYP2C subfamily comprises about 20% of all of the cytochrome P450s in the liver.12 At least 6 different CYP2C isozymes have been characterized, each having greater than 80% homology with distinct but overlapping substrate specificity. Prostaglandins and sex steroids are important endogenous substrates of the CYP2C subfamily. The most abundant enzyme in this subfamily, CYP2C9, is responsible for the breakdown of a number of drugs including ASA and many of the nonsteroidal anti-inflammatory drugs, sulfonamides, phenytoin and S-warfarin (the more active enantiomer of warfarin). CYP2C19 is involved in the metabolism of diazepam, omeprazole and the tricyclic antidepressants. Both CYP2C9 and CYP2C19 are polymorphic, meaning the expression of these enzymes is under strong genetic influence and some individuals have markedly deficient activities. Indeed, 3% of white people and 20% of all those of Japanese descent lack CYP2C19 and are unable to metabolize diazepam and omeprazole by the usual pathways.13,14 However, since many of the enzymes in this family have overlapping substrate specificities, it is unusual to see excessive or adverse drug effects even in people completely deficient in CYP2C19.15 Serious interactions occur predominantly with drugs that have a low therapeutic index such as warfarin or phenytoin.10

CYP2D6 accounts for only 4% of hepatic CYP enzymes,12 but is more unique in its metabolic profile. Important substrates for this enzyme include tricyclic antidepressants, selective serotonin reuptake inhibitors, neuroleptics, opioid analgesics and several of the ß-adrenergic blockers. Seven to 10% of white people and 3% of black and oriental people are known to be deficient in the CYP2D6 enzyme, the so-called sparteine­debrisequine, poor metabolizer polymorph.13,14 These individuals show great variability in clinical response (up to 1000-fold) and commonly have adverse effects to standard doses of drugs metabolized by this enzyme. Also, they are unable to convert codeine, oxycodone and hydrocodone to their active metabolites16 and thereby derive little or no analgesic benefit from oral morphine analogues. Levels of CYP2D6 are not affected by age, sex or smoking status.17 Inhibitors are quinidine, ketoconazole and most antidepressants and neuroleptics, and there are no known inducers of this enzyme.

The CYP3A subfamily, like CYP2D6, is involved in the metabolism of a large number drugs and other chemicals and is involved in many drug­drug and drug­food interactions. It is the most abundant of all of the P450s in the human liver (25%­28%, but sometimes as high as 70%) and is widely expressed throughout the gastrointestinal tract, kidneys and lungs.12 More than 150 drugs are known substrates of CYP3A4, the major CYP3A isozyme, including many of the opiate analgesics, steroids, antiarrhythmic agents, tricyclic antidepressants, calcium-channel blockers and macrolide antibiotics. Although several substrates show age-dependent reductions in elimination, the enzyme itself does not appear to be altered.18 Also, sex-related effects are small and probably not important. Ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, fluvoxamine, fluoxetine, nefazodone, cyclosporine and dihydroxybergamottin and various substances found in grapefruit juice, green tea and other foods are potent inhibitors of CYP3A4 and are known to be responsible for many drug interactions.10,15 Terfenadine, astemizole, cisapride, cyclosporine and many of the hydroxymethylglutaryl ­ coenzyme A (HMG­CoA) reductase inhibitors are potentially toxic drugs or drugs susceptible to large changes in concentration following enzyme inhibition and, therefore, are candidates for serious interactions with other substrates of CYP3A4.10 These interactions can have serious clinical consequences.

http://www.nlc-bnc.ca/eppp-archive/100/201/300/cdn_medical_association/cmaj/vol-161/issue-10/1281.ht...

http://ragingbull.lycos.com/mboard/boards.cgi?board=EXTI&read=24249