1. Pyridoxal Phosphate (PLP) is a Cofactor for Many Enymes Histidine decarboxylase Pyridoxal phosphate (PLP) PLP Histidine Histamine Binding to H 1 receptors: Allergy symptoms Binding to H2 receptors: Gastric acid secretion Example: Decarboxylation of amino acids

2. PLP-Mediated Histidine Decarboxylation Proceeds via an Imine Intermediate PLP Histidine Histamine Histidine-PLP imine decarboxylation Histamine-PLP imine

3. H 1 receptor antagonists: antihistamines H 2 receptor antagonists inhibit gastric secretion Tagamet® Cimetidine Benadryl® Diphenhydramine Marketed Histamine Receptor Antagonists

4. Celebrex® (Celecoxib) Selective COX-2 inhibitor Celebrex® Is a Pyrazole-Containing NSAID Synthesis

5. Acetaminophen (Tylenol®) Acetaminophen Metabolism Proceeds Through Multiple Pathways Glucuronidation Sulfation Oxidation NAPQI Glucuronide and sulfate are more polar and thus more water soluble, facilitating excretion

6. Under Normal Conditions NAPQI Is Detoxified by Glutathione The NAPQI metabolite is an electrophilc intermediate which can undergo conjugate addition NAPQI Glutathione (GSH) Conjugate addition (1,4-addition)

7. If Glutathione Stores Become Depleted NAPQI Accumulates and Can React with Proteins The NAPQI metabolite is an electrophilc intermediate which can undergo conjugate addition NAPQI Cysteine residue of protein Conjugate addition (1,4-addition) Alkylation leads to disruption of protein function