various phase 2 reactions of drug metabolism with examples with their chemical reactions

Phase 2 reactions of drug metabolism, also known as conjugation reactions, involve the covalent attachment of small hydrophilic molecules to drugs or their metabolites from Phase 1 reactions, increasing their water solubility and facilitating their excretion. The main types of Phase 2 reactions include glucuronidation, sulfation, acetylation, methylation, and conjugation with amino acids and glutathione. Here are some examples along with their chemical reactions:

1. Glucuronidation

Enzyme: UDP-glucuronosyltransferase (UGT)
Co-factor: Uridine diphosphate glucuronic acid (UDPGA)

Example: Glucuronidation of morphine

$\text{Morphine}+\text{UDPGA}\stackrel{\text{UGT}}{\to }\text{Morphine-3-glucuronide}+\text{UDP}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{Morphine}}& {\displaystyle :{\mathrm{C}}_{17}{\mathrm{H}}_{19}\mathrm{N}{\mathrm{O}}_3}\\ {\displaystyle \text{UDPGA}}& {\displaystyle :{\mathrm{C}}_{15}{\mathrm{H}}_{24}{\mathrm{N}}_2{\mathrm{O}}_{18}{\mathrm{P}}_2}\\ {\displaystyle \text{Morphine-3-glucuronide}}& {\displaystyle :{\mathrm{C}}_{23}{\mathrm{H}}_{27}\mathrm{N}{\mathrm{O}}_9}\\ {\displaystyle \text{UDP}}& {\displaystyle :{\mathrm{C}}_9{\mathrm{H}}_{12}{\mathrm{N}}_2{\mathrm{O}}_{12}{\mathrm{P}}_2}\end{array}$$

2. Sulfation

Enzyme: Sulfotransferase (SULT)
Co-factor: 3'-Phosphoadenosine-5'-phosphosulfate (PAPS)

Example: Sulfation of acetaminophen

$\text{Acetaminophen}+\text{PAPS}\stackrel{\text{SULT}}{\to }\text{Acetaminophen sulfate}+\text{PAP}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{Acetaminophen}}& {\displaystyle :{\mathrm{C}}_8{\mathrm{H}}_9\mathrm{N}{\mathrm{O}}_2}\\ {\displaystyle \text{PAPS}}& {\displaystyle :{\mathrm{C}}_{10}{\mathrm{H}}_{15}{\mathrm{N}}_5{\mathrm{O}}_{13}\mathrm{S}}\\ {\displaystyle \text{Acetaminophen sulfate}}& {\displaystyle :{\mathrm{C}}_8{\mathrm{H}}_9\mathrm{N}{\mathrm{O}}_5\mathrm{S}}\\ {\displaystyle \text{PAP}}& {\displaystyle :{\mathrm{C}}_{10}{\mathrm{H}}_{14}{\mathrm{N}}_5{\mathrm{O}}_{10}\mathrm{P}}\end{array}$$

3. Acetylation

Enzyme: N-acetyltransferase (NAT)
Co-factor: Acetyl-CoA

Example: Acetylation of isoniazid

$\text{Isoniazid}+\text{Acetyl-CoA}\stackrel{\text{NAT}}{\to }\text{N-acetylisoniazid}+\text{CoA}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{Isoniazid}}& {\displaystyle :{\mathrm{C}}_6{\mathrm{H}}_7{\mathrm{N}}_3\mathrm{O}}\\ {\displaystyle \text{Acetyl-CoA}}& {\displaystyle :{\mathrm{C}}_{23}{\mathrm{H}}_{38}{\mathrm{N}}_7{\mathrm{O}}_{17}{\mathrm{P}}_3\mathrm{S}}\\ {\displaystyle \text{N-acetylisoniazid}}& {\displaystyle :{\mathrm{C}}_8{\mathrm{H}}_9{\mathrm{N}}_3{\mathrm{O}}_2}\\ {\displaystyle \text{CoA}}& {\displaystyle :{\mathrm{C}}_{21}{\mathrm{H}}_{36}{\mathrm{N}}_7{\mathrm{O}}_{16}{\mathrm{P}}_3\mathrm{S}}\end{array}$$

4. Methylation

Enzyme: Methyltransferase
Co-factor: S-adenosylmethionine (SAM)

Example: Methylation of catecholamines (e.g., norepinephrine)

$\text{Norepinephrine}+\text{SAM}\stackrel{\text{Methyltransferase}}{\to }\text{Normetanephrine}+\text{SAH}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{Norepinephrine}}& {\displaystyle :{\mathrm{C}}_8{\mathrm{H}}_{11}\mathrm{N}{\mathrm{O}}_3}\\ {\displaystyle \text{SAM}}& {\displaystyle :{\mathrm{C}}_{15}{\mathrm{H}}_{22}{\mathrm{N}}_6{\mathrm{O}}_5\mathrm{S}}\\ {\displaystyle \text{Normetanephrine}}& {\displaystyle :{\mathrm{C}}_9{\mathrm{H}}_{13}\mathrm{N}{\mathrm{O}}_3}\\ {\displaystyle \text{SAH}}& {\displaystyle :{\mathrm{C}}_{14}{\mathrm{H}}_{20}{\mathrm{N}}_6{\mathrm{O}}_5\mathrm{S}}\end{array}$$

5. Amino Acid Conjugation

Enzyme: Various enzymes depending on the amino acid
Co-factor: Amino acids (e.g., glycine, glutamine)

Example: Conjugation of benzoic acid with glycine

$\text{Benzoic acid}+\text{Glycine}\stackrel{\text{Acyl-CoA synthetase}}{\to }\text{Hippuric acid}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{Benzoic acid}}& {\displaystyle :{\mathrm{C}}_7{\mathrm{H}}_6{\mathrm{O}}_2}\\ {\displaystyle \text{Glycine}}& {\displaystyle :{\mathrm{C}}_2{\mathrm{H}}_5\mathrm{N}{\mathrm{O}}_2}\\ {\displaystyle \text{Hippuric acid}}& {\displaystyle :{\mathrm{C}}_9{\mathrm{H}}_9\mathrm{N}{\mathrm{O}}_3}\end{array}$$

6. Glutathione Conjugation

Enzyme: Glutathione S-transferase (GST)
Co-factor: Glutathione (GSH)

Example: Conjugation of N-acetyl-p-benzoquinone imine (NAPQI, a toxic metabolite of acetaminophen) with glutathione

$\text{NAPQI}+\text{GSH}\stackrel{\text{GST}}{\to }\text{Mercapturic acid conjugate}$

Chemical Reaction:

$$\begin{array}{rl}{\displaystyle \text{NAPQI}}& {\displaystyle :{\mathrm{C}}_8{\mathrm{H}}_7\mathrm{N}{\mathrm{O}}_2}\\ {\displaystyle \text{GSH}}& {\displaystyle :{\mathrm{C}}_{10}{\mathrm{H}}_{17}{\mathrm{N}}_3{\mathrm{O}}_6\mathrm{S}}\\ {\displaystyle \text{Mercapturic acid conjugate}}& {\displaystyle :{\mathrm{C}}_{13}{\mathrm{H}}_{19}{\mathrm{N}}_3{\mathrm{O}}_6\mathrm{S}}\end{array}$$

These Phase 2 reactions significantly enhance the solubility of drugs, making it easier for the body to eliminate them through renal or biliary excretion.