Research on the various enzymes responsible for metabolizing drugs in the human liver is shedding light on the effects of aging on this important process. Here's an explanation of what scientists have learned over the past decade.
| L. Michael Posey |
CYP 4B1. 2D6. 1A1. 3A3-5. Even for pharmacists young enough to remember the cytochrome P-450 system from pharmacy school, the presentation of these cryptic designations for various metabolic enzyme systems can be confusing.
But for consultant pharmacists, this information is especially critical for two reasons. One, the frail old-old patients common in nursing homes are very susceptible to metabolic changes resulting from drug-drug interactions, and these may be understood better through study of the metabolic isoforms. Second, some age-related changes have been identified in the isoforms.
This article will present the nomenclature and basic characteristics of the better-studied human isoform systems and present the limited information available about pharmacokinetics in the elderly. It relies heavily on Pelkonen and Breimer1 for information about the hepatic isoenzymes; much of the material in this article not referenced to other sources has been obtained from that review article.
Designations for Hepatic Isoforms Active in Drug Metabolism
In its simplest form, the isoform nomenclature system is nothing more than a series of laboratory code names for enzymes present in the liver or other places in the body and responsible for metabolism (oxidation, dealkylation, or hydroxylation) of drugs and other foreign chemicals. Following the CYP code for cytochrome P450, the first number represents families of enzymes with more than 40% identity in amino acid sequence. Subfamilies are designated by the letters in the next position, and the individual enzyme is denoted by the final number.2
Much of the work elucidating the presence and basic functions of the hepatic microsomal enzyme isoforms was conducted in animal models, especially in rats. Thus, confusion can arise because of differences in assignment of code numbers in rats, other animal species, and humans for the same enzyme. Examples of this problem are shown in Table 1 for the 11 isoforms identified in humans through 1994.
Table 1. Interspecies Differences in Code Designations for 11 Human Isoformsa
| Ethoxyresorufin O-dealkylation | ||||
| Phenacetin O-dealkylation | ||||
| Coumarin 7-hydroxylation | ||||
| Benzphetamine N-demethylation | ||||
| S-Mephenytoin 4-hydroxylation | ||||
| Hexobarbital 1a-hydroxylation | ||||
| Tolbutamide hydroxylation | ||||
| Desbrisoquine 4-hydroxylation | ||||
| Aniline p-hydroxylation | ||||
| Nifedipine oxidation | ||||
| Lidocaine N-deethylation | ||||
a Adapted from reference 1.
Moreover, some drugs may be metabolized by more than one of the systems (that is, the enzymes lack specificity for some substrates). Thus, even when one enzyme system may be induced or inhibited by an interacting drug, the metabolism of a second drug may (or may not) proceed without substantial change.
Table 2 presents basic biochemical information about the better-studied isoenzymes identified in human liver and extrahepatic tissues. These isoform families are responsible for much of the drug metabolism observed in people. Here is a brief description of each family.
Table 2. Isoforms of the Human P-450 System Active in Drug Metabolisma
| 3A3-5 | Liver and extrahepatic | Nifedipine, erthromycin, cyclosporine, cortisol | Ketoconazole | Phenobarbital, rifampicin, dexamethasone |
| 2C8-10 | Liver | Tolbutamine, s-warfarin, phenytoin | Sulfaphenazole | Phenobarbital, rifampicin |
| 1A2 | Liver | Phenacetin, caffeine, theophylline | Furafylline | Omeprazole, smoking |
| 2C18 | Liver? | Mephenytoin | Phenobarbital, rifampicin | |
| 2D6 | Liver | Dextromethorphan, sparteine, debrisoquine | Quinidine | |
| 2A6 | Liver | Coumarin | Phenobarbital, rifampicin | |
| 2E1 | Liver and extrahepatic | Chloroxazone | Tetrahydrofurane | |
| 1A1 | Extrahepatic | Tetrahydrofurane | Ethanol, isoniazide, diabetes | |
| 2B6 | Liver |
a Listed inorder of approximate amounts of each isoform in human
liver.
CYP 3A
The 3A family is present in the largest quantities in human liver, and it has been identified in extrahepatic tissues such as the gastrointestinal tract. Three adult 3A isoforms have clear differences but overlap in their specificity considerably. The system can be induced by phenobarbital, rifampicin, macrolide antibiotics, and glucocorticoids. Among the reactions catalyzed by 3A isoforms are erythromycin N-demethylation, nifedipine oxidation, 6b-hydroxylation, and lidocaine N-demethylation. The effect of grapefrut juice on metabolism of dihydropyridine calcium-channel blockers results from 3A inhibition by flavinoids in the drink.
CYP 2D6
The 2D6 isoenzyme, debrisoquine hydroxylase, is important clinically for several reasons3:
Table 3. Selected Drugs Metabolized by Cytochrome P-450 Isoform 2D6 (desbrinoquine hydroxylase)
Neuroleptics
Chlorpromazine
Fluphenazine
Perphenazine
Risperidone
Antidepressants
Imipramine
Desipramine
Nortriptyline
Clomipramine
Paroxetine
Beta blockers
Some antiarrhythmic agents
Some oncolytic agents
The genetic locus producing decreased 2D6 activity cosegregates with the gene for sparteine oxidation. As a result, numerous drugs are affected by the two polymorphically expressed enzymes.4
CYP 1A
Two major isoforms are grouped in family 1A. Ironically, 1A1 was one of the first identified, yet its presence in liver tissue is questionable. It occurs primarily in extrahepatic tissue such as placenta.
1A2 is a major isoform that is inducible by tobacco smoking. Phenacetin O-dealkylation, caffeine 3-demethylation, and theophylline 8-hydroxylation are among the reactions catalyzed by CYP 1A2.
The 1A2 isoform is one of the few expressed consistently across animal models. Animal data thus translate into human experience quite well.
CYP 2A6 and 2B6
Each of these isoforms is under study at this time. Using compounds called probe drugs, scientists are elucidating the properties of these enzymes in people. Probes are drugs that are metabolized solely and specifically by the enzyme system under study. By establishing a clear baseline using the probe, changes in metabolism can be measured by introducing inhibitors, inducers, and other substrates into the system.
Coumarin 7-hydroxylation has proven relatively specific for 2A6, while 2B6 is induced by phenobarbital and other antiepileptic drugs.
The 2B6 isoform is responsible for increased clearance of several drugs after phenobarbital-type induction in people. 2A6 catalyzes the oxidative metabolism of coumarin derivatives, including psoralens and aflatoxin B1.1
CYP 2C
The 2C system has been well studied in rat models, but the differences between rodent and human enzymes are marked for these isoenzymes. 2C8-10 are the best known human variants, and they metabolize mephenytoin, phenytoin, and tolbutamide. However, actions have not been attributed to specific isoforms, and gender differences further complicate research into the 2C family.1
CYP 2E1
The 2E1 system is also in need of specific study, particularly because it is important in hepatotoxicity and carcinogenesis caused by chemicals such as benzene and nitrosamines. The isoform, responsible for metabolism of more than 60 known substances, can be affected by alcohol consumption, drugs such as isoniazid, and conditions such as diabetes, ketonemia, and obesity.1 Among the few known probes for 2E1 are the carcinogens dimethylnitrosamine and p-nitrophenol, which are, of course, of no use in human research.
Relationship between Pharmacogenetics and Gerontokinetics
For consultant pharmacists, the knowledge regarding the hepatic microsomal isoenzymes is generally applied in the complex elderly patient. An earlier suspicion-that a uniform age-related decline in oxidative and demethylative activity accompanied aging-has been disproven in people, but other complications make sound pharmacokinetic analyses critically important in the elderly.3
Drug distribution is influenced by age-related changes in metabolism, distribution, and excretion. Between ages 20 and 75, the percentage of fat relative to lean body mass and total body water increases 25%-45%. The volume of distribution of lipid-soluble drugs increases as a result, as does half-life. Hepatic blood flow is 40% lower in people 65 years or older, compared with 25-year-olds. The hepatic first-pass effect is reduced, again extending half-lives. Excretion through the kidney declines as the number of functioning nephrons decreases. Many elderly are consuming numerous medications concurrently, have diminished function and less reserve in critical systems such as heart and kidneys, and have heightened sensitivity to drug responses.3
Biochemistry: Altering the Status Quo in Clinical Medicine
Combined with the newfound knowledge of these hepatic isoforms, aging-related changes can produce marked differences in drug concentrations, half-lives, excretion rates, and clinical response. As biotechnology and improved analytic methods increase the power of tools in the biochemists' arsenal, clinicians can look forward to extensive and precise knowledge of the actions of many enzymes extant in the human liver.
References
1. Pelkonen O, Breimer DD. Role of environmental factors in the pharmacokinetics of drugs: considerations with respect to animal models, P-450 enzymes, and probe drugs. In: Welling PG, Balant LP, eds. Pharmacokinetics of drugs. Berlin: Springer-Verlag, 1994: 289-332.
2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother 1995; 29:619-24.
3. Pollock B. Clinical relevance of pharmacogenetic variations for geriatric psychopharmacology. Drug Info J 1996; 30: 669-74.
4. Kroemer HK, Mikus G, Eichelbaum M. Clinical relevance of pharmacogenetics. In: Welling PG, Balant LP, eds. Pharmacokinetics of drugs. Berlin: Springer-Verlag, 1994: 269-70.
L. Michael Posey is Academics Editor, TCP.
Copyright© 1996, American Society of Consultant Pharmacists, Inc. All rights reserved.