The Dominance, Not Dictatorship, of CYP450
For many years, the spotlight in pharmacology has been on the liver's cytochrome P450 (CYP450) enzyme system. These heme-containing enzymes, named for their absorption peak at 450 nanometers, are found predominantly in liver cells but also in other tissues like the intestines and kidneys. They perform Phase I oxidation reactions on a wide range of substrates, including drugs, steroids, and other foreign chemicals. The system's importance cannot be overstated; certain key isoforms, such as CYP3A4 and CYP2D6, are responsible for metabolizing up to 90% of drugs in clinical use. However, this dominance has led to a misunderstanding that these enzymes are the only metabolic mechanism. They are the major players, but they are not the sole arbiters of drug metabolism.
Non-CYP Pathways: A Diverse Metabolic Arsenal
Drug metabolism is a complex, multi-stage process involving numerous enzymatic systems. When a drug is not a substrate for CYP450, or when the CYP450 pathway is saturated or inhibited, other non-CYP enzymes step in. These pathways are categorized into Phase I and Phase II reactions.
Phase I Reactions: Beyond CYP450
While CYP450 enzymes are the most well-known catalysts for Phase I oxidation, other non-CYP enzymes also carry out modification reactions, including oxidation, reduction, and hydrolysis. Key examples include:
- Flavin Monooxygenases (FMOs): Found primarily in the liver, FMOs use flavin as a cofactor to oxidize nitrogen, sulfur, and phosphorus-containing compounds. They are a critical detoxification pathway for many xenobiotics.
- Monoamine Oxidases (MAOs): These enzymes are crucial for metabolizing endogenous monoamines like dopamine, serotonin, and norepinephrine, as well as exogenous monoamines. MAO inhibitors are an important class of antidepressants.
- Aldehyde Oxidase (AO): AO is a cytosolic enzyme that metabolizes aldehydes and certain nitrogen-containing heterocycles. It played a crucial role in the metabolism of SGX523, a c-Met inhibitor, which demonstrated different metabolic profiles in animal models versus humans due to the presence of AO.
- Esterases: These enzymes catalyze the hydrolysis of ester and amide linkages and include carboxylesterases (CEs) and cholinesterases. A significant percentage of drugs are substrates for hydrolases, particularly those designed as prodrugs.
Phase II: The Conjugation Specialists
Many drugs and Phase I metabolites proceed to Phase II, where they are conjugated with an endogenous substance to become more water-soluble for easier excretion. Non-CYP enzymes are the central players here. The main conjugation reactions involve:
- UDP-glucuronosyltransferases (UGTs): UGTs add a glucuronic acid molecule to a drug or metabolite. This is a very common non-CYP pathway, with UGTs being the most prevalent non-CYP enzyme family involved in drug metabolism.
- Sulfotransferases (SULTs): SULTs catalyze the transfer of a sulfate group. This pathway is particularly important for the metabolism of hormones and many medications.
- N-acetyltransferases (NATs): These enzymes transfer an acetyl group and exhibit significant genetic variability that impacts how individuals metabolize certain drugs.
Drugs That Bypass the CYP450 System
Many drugs bypass the CYP450 system entirely, relying on the alternative enzymes and pathways described above. Examples of drugs that are not significantly metabolized by the CYP450 system include:
- Water-soluble Beta-blockers: Sotalol, atenolol, and nadolol are primarily eliminated by renal excretion and are less prone to interactions involving CYP450 inhibition or induction.
- Certain Angiotensin II Receptor Blockers (ARBs): Valsartan, eprosartan, and candesartan are not metabolized by the CYP450 system, which simplifies their interaction profile compared to other ARBs.
- Some Prodrugs: Certain prodrugs rely on non-CYP enzymes for activation. For instance, many prodrugs are activated by hydrolases (esterases).
- Directly Excreted Drugs: Highly hydrophilic drugs, including some antibiotics and renally-cleared agents, may be excreted by the kidneys directly with little or no prior metabolism. Paliperidone, an atypical antipsychotic, is one example where action is terminated principally by renal excretion.
Comparison of CYP-Mediated vs. Non-CYP-Mediated Metabolism
| Feature | CYP-Mediated Metabolism | Non-CYP-Mediated Metabolism (e.g., UGTs, Esterases) |
|---|---|---|
| Primary Location | Predominantly liver microsomes; also intestine, kidneys, lungs. | Can occur in liver (microsomes and cytosol), plasma, kidneys, intestines. |
| Dominant Reaction | Oxidation (Phase I). | Conjugation (Phase II), Hydrolysis, Reduction (Phase I). |
| Enzymes Involved | CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc. | UGTs, SULTs, MAOs, FMOs, Esterases, AO, etc. |
| Genetic Variability | High prevalence of polymorphisms affecting enzyme activity (poor, intermediate, extensive, ultra-rapid metabolizers). | Polymorphisms also exist (e.g., UGTs, NATs) and can significantly impact drug response. |
| Drug-Drug Interactions | Frequent and well-studied interactions involving enzyme inhibition or induction. | Interactions can occur through competition for non-CYP enzymes or transporters. |
Why Understanding All Pathways is Crucial
Understanding that not all drugs are metabolized by CYP450 enzymes has critical implications in clinical practice and drug development. For clinicians, it means considering a wider range of potential drug-drug interactions (DDIs). An interaction may still occur if a co-administered drug inhibits a non-CYP enzyme like UGTs, or if it competes for excretion via renal transporters. For drug developers, designing drugs that predominantly use non-CYP pathways or direct excretion can reduce the risk of problematic DDIs and variable patient responses associated with CYP450 genetic polymorphisms. The FDA even recommends investigating non-CYP pathways if they are believed to contribute significantly to a drug's elimination.
Moreover, a drug's elimination can be influenced by many factors beyond genetics and enzymatic pathways, including disease states (especially liver or kidney dysfunction), age, diet, and concurrent medications. In elderly patients, for example, a decline in liver function may reduce metabolism, requiring dose adjustments.
Conclusion: The Bigger Picture of Drug Metabolism
The question, "Are all drugs metabolised by CYP450?" prompts a deeper appreciation for the full scope of drug metabolism. While the CYP450 system is profoundly important and handles the bulk of Phase I oxidative metabolism, it is not an exclusive pathway. A rich and diverse network of non-CYP enzymes, including Phase II conjugating enzymes, provides alternative routes for biotransformation and elimination. Many drugs, particularly water-soluble compounds, are primarily cleared through other enzymatic systems or directly by the kidneys. Recognizing the entire picture of drug metabolism is crucial for predicting pharmacokinetics, preventing adverse drug reactions, and advancing the development of safer, more effective therapeutics.
For a deeper understanding of drug metabolism and elimination pathways, consult the Merck Manuals professional version.
