PMCOL 306 Enzyme in phase 1 and 2 Metabolism

CYP2D6

- Metabolizes 25% of commonly prescribed drugs like antidepressants, antiarrhythmics, and beta-adrenergic antagonists

- Highly polymorphic

CYP3A4

- Most abundant CYP in liver, metabolizes over 50% of clinically used drugs

- Substrates range from small drugs like Dapsone to large ones like cyclosporine

- Grapefruit is an inhibitor

CYP1A2

- Metabolizes 5% of marketed drugs like clozapine, olanzapine, and theophylline

- activity is induced by smoking, so smokers will have higher clearance of stated drugs

Flavin-Containing Monooxygenases (FMOS)

- six major families, FMO3 is most abundant in the liver

- Metabolizes nicotine, H2 receptor antagonists, antipsychotics, and antiemetics

- Minor contribution to drug metabolism

- Not readily inhibited or induced by xenobiotic receptors

Uridine diphosphate-glucuronosyltransferase (UGTs)

- Undergo glucuronidation

- Catalyze transfer of glucronic acid form UDP-GA

- Found in GI tract and liver

- Substrates include angrodens, estrogens, mineralcorticoids, glucocortiocids, thyroxine, bile acids, retinoids, and bilirubin

- UGT2 has greatest specificity for endogenous substances

- Alcohol and smoking linked to variability

Sulfotrasnferases (SULTs)

- located in cytosol of hepatocytes

- Conjugate sulfate derived from PAPS

- SULT1 is major isoform in xenobiotic metabolism

- Catalyzes sulfation of phenolic molecules like acetaminophen and minoxidil

N-acetyl transferase

- NAT1 and 2

- Acetylation

- Occurs in Kupffer cells in liver

- involves addition of acetylene group from acetylene coenzyme A

- Common path for aromatic amines, hydrazines and sulphonamide antibacterial drugs

- Very polymorphic

- There are fast and slow acetylators

Glutathione S-transferase

- Glutathione conjugation

- Soluble enzyme in liver and kidney

- Catalyzes transfer of glutathione to reactive electrophiles

- Serves to protect cellular macromolecules from interacting with electrophiles containing -O, -N, and -S