Enzymes play a crucial role in detoxifying harmful substances in our bodies. They're like tiny cleanup crews, breaking down toxins and making them easier to get rid of. This process happens in two main stages, each with its own set of enzyme helpers.

Phase I enzymes, like cytochrome P450, start the cleanup by adding oxygen to toxins. Phase II enzymes then step in, attaching other molecules to make the toxins more water-soluble. This teamwork helps our bodies flush out dangerous chemicals more easily.

Phase I Enzymes

Cytochrome P450 Monooxygenases

• Cytochrome P450 (CYP) enzymes are a superfamily of heme-containing monooxygenases that catalyze the oxidation of various endogenous and exogenous compounds
• CYP enzymes are predominantly found in the endoplasmic reticulum of liver cells (hepatocytes) but are also present in other tissues such as the intestine, kidney, and lung
• These enzymes introduce functional groups (hydroxyl, carboxyl, or epoxide) into the substrate molecule, making it more polar and susceptible to further metabolism by Phase II enzymes
• CYP enzymes require NADPH and molecular oxygen for their catalytic activity
• Examples of CYP-mediated reactions include hydroxylation (addition of -OH group), epoxidation (formation of epoxide), and dealkylation (removal of alkyl groups)
• The most important CYP subfamilies involved in xenobiotic metabolism are CYP1, CYP2, and CYP3, with CYP3A4 being the most abundant isoform in the human liver

Carboxylesterases and Epoxide Hydrolases

• Carboxylesterases are enzymes that hydrolyze ester- and amide-containing compounds, such as drugs (procaine, heroin), pesticides (pyrethroids), and plasticizers (phthalates)
• These enzymes are found in the endoplasmic reticulum of liver, intestine, and other tissues
• Carboxylesterases convert ester and amide groups into carboxylic acids, increasing the water solubility of the compound and facilitating its elimination
• Epoxide hydrolases catalyze the hydrolysis of epoxides, which are highly reactive and potentially toxic metabolites formed by CYP enzymes
• Epoxide hydrolases convert epoxides into less reactive and more water-soluble dihydrodiols
• Examples of compounds metabolized by epoxide hydrolases include polycyclic aromatic hydrocarbons (benzo[a]pyrene), and certain drugs (carbamazepine)

Phase II Enzymes

Glucuronidation and Sulfation

• UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid to various substrates, including drugs (morphine, acetaminophen), hormones (estrogens, thyroid hormones), and bilirubin
• Glucuronidation increases the water solubility and molecular weight of the substrate, facilitating its excretion via bile or urine
• UGTs are localized in the endoplasmic reticulum of liver, intestine, kidney, and other tissues
• Sulfotransferases (SULTs) catalyze the transfer of a sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to various substrates, such as hormones (estrogens, thyroid hormones), neurotransmitters (dopamine, serotonin), and drugs (acetaminophen, minoxidil)
• Sulfation generally results in the inactivation of the substrate and increases its water solubility, promoting its elimination

Glutathione and Acetyl Conjugation

• Glutathione S-transferases (GSTs) catalyze the conjugation of reduced glutathione (GSH) to electrophilic compounds, such as drugs (acetaminophen), carcinogens (aflatoxin B1), and products of oxidative stress (lipid peroxides)
• GST-mediated conjugation detoxifies reactive electrophiles and protects cellular macromolecules from damage
• GSTs are present in the cytosol and membranes of liver, intestine, kidney, and other tissues
• N-acetyltransferases (NATs) catalyze the transfer of an acetyl group from acetyl-coenzyme A to aromatic amines and hydrazines, such as drugs (isoniazid, sulfonamides) and carcinogens (benzidine, 4-aminobiphenyl)
• Acetylation can result in either the activation or inactivation of the substrate, depending on the compound
• NATs are cytosolic enzymes found in liver, intestine, and other tissues, and their activity exhibits genetic polymorphism, leading to "slow" and "fast" acetylator phenotypes