Biochemistry & Pharmacology: Open Access
Open Access

Phase II Enzymes: Conjugation Reactions and Drug Solubility Enhancement

Radwa Mahfouz^{* *}Correspondence: Radwa Mahfouz, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt, Email:

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About the Study

The human body uses enzymes to facilitate complex biochemical processes that influence the development and effectiveness of pharmacological molecules. Enzymes are need to drug metabolism in this process. Enzymes involved in drug metabolism are primarily found in the liver, although other tissues such as the intestines and kidneys also contribute. The liver, however, remains the main region due to its high concentration of enzymes and its role in detoxification and elimination of external components, including drugs. These enzymes are typically categorized into two main groups. They are phase I and phase II enzymes.

Phase I enzymes, such as Cytochrome P450 (CYP) enzymes, initiate drug metabolism by introducing or activating functional groups on the drug molecule through oxidation, reduction, or hydrolysis reactions. This phase is critical as it often converts lipophilic drugs into more hydrophilic forms, facilitating their elimination via urine or bile. CYP enzymes are extremely varied and exhibit substrate specificity, meaning different enzymes may metabolize specific classes of drugs.

The kinetics of phase I enzymes are often characterized by Michaelis-Menten kinetics, where the rate of drug metabolism (v) depends on the drug concentration, the maximum velocity of the enzyme-substrate complex (Vmax), and the Michaelis constant (Km), which reflects the affinity of the enzyme for its substrate. High Km values indicate low affinity, requiring higher substrate concentrations to achieve maximum velocity, while low Km values indicate high affinity.

Phase II enzymes primarily involve conjugation reactions where functional groups, introduced in phase I, are conjugated with endogenous molecules such as glucuronic acid, sulfate, or amino acids. This conjugation often increases the water solubility of the drug, facilitating its excretion. Phase II enzymes include Uridine 5'- diphospho-Glucuronosyl Transferase (UGTs), sulfotransferases, and Glutathione S-Transferases (GSTs), each with specific substrates and roles in drug metabolism.

The kinetics of phase II enzymes also follows Michaelis-Menten kinetics, albeit with different parameters specific to each enzymesubstrate pair. These enzymes frequently have saturable kinetics, which means that when substrate concentrations are high, enzyme saturation causes the rate of metabolism to a low point. Pharmacokinetic parameters such as clearance, half-life, and bioavailability are influenced by enzyme kinetics. Clearance, for instance, directly relates to the enzymatic activity responsible for metabolizing the drug. Drugs metabolized by enzymes with high Vmax values will be cleared more rapidly from the body compared to drugs metabolized by enzymes with lower Vmax values.

Drug-drug interactions also heavily depend on enzyme kinetics. Enzyme induction or inhibition can change the metabolic rate of drugs, leading to either reduced efficacy or increased toxicity. Inducers such as rifampicin can increase the expression of Cytochrome P450 (CYP) enzymes, increasing the metabolism of co-administered drugs. Comparatively, inhibitors like fluoxetine can suppress enzyme activity, prolonging the presence of drugs in the body.

Variability in enzyme kinetics among individuals also contributes to differences in drug metabolism and response. Genetic polymorphisms in enzymes such as CYPs can lead to altered enzyme activity, affecting drug metabolism rates among different populations. For example, individuals with a genetic variant leading to reduced Cytochrome P450 Family 2 Subfamily D Member 6 (CYP2D6) activities may metabolize certain drugs, like codeine, differently, potentially leading to ineffective treatment or toxicity. Factors beyond genetics, such as age, sex, and disease states, can also influence enzyme kinetics. Aging, for instance, is associated with reduced liver function and enzyme activity, leading to slower drug metabolism in elderly patients. Disease conditions affecting liver function, such as cirrhosis, hepatitis, or liver cancer, can similarly impair enzyme activity, affecting drug metabolism and necessitating dosage adjustments or alternative therapies.