1. Medical Biochemistry Robert F. Waters, PhD Cytochrome P450 System (Introduction)

2. Introduction Formation of metabolic intermediates Xenobiotics –Plants –Poisons –Toxins Protein sites (Genetic Control) –Molecular families –Pseudogenes –Example: 3A4 acetominophen, Lovastatin, codeine, valium, etc. FMN, Fe, S (NAC), Cu, Zn Pseudogenes ? Polymorphisms (Familial)

3. Cytochrome P450 System Cytochrome P450 proteins in humans are drug metabolizing enzymes and enzymes that are used to make cholesterol, steroids and other important lipids such as prostacyclins and thromboxane A2. These last two are metabolites of arachidonic acid. (See Next Page) Induction of some P450s is a risk factor in several cancers since these enzymes can convert procarcinogens to carcinogens. –However….may also be used in cancer. Cancer patient is given a prodrug (Non-toxic) Inject a patient with a vector that has CYTP450 gene to convert prodrug to drug Drug kills cancer cells Administer reductase to patient to neutralize drug

4. Acetylsalicylates –Detoxification (Glucuronic Acid, Glycine) –Attaches to albumen Note teratogenicity –Inhibits prostaglandin synthesis Inhibits inflammatory response Inhibits vasodilation –Inhibits Thromboxane A 2 Inhibits coagulation –Stimulates LT 4

5. Acetominophen Poisoning and GSH Note: Oxidation (gain oxygen, lose e -, lose H + ) –Produces free radicals Acetaminophen Poisoning –Depletes Erythrocyte and Hepatic GSH –Oxidizes Hb so Fe ++ becomes Fe +++ Called MetHb (Methemoglobinemia) –Cannot bind oxygen –Depletes hepatic glucuronyl transferase –Delayed response!

6. Diseases Associated with Genetic Lesions Some diseases associated with Cyt gene mutations: –Congenital glaucoma –Defects in Sodium metabolism(Aldosterone) –Neonatal liver disease –Hypercholesterolemia (Resistant to statin Drugs) –Glucocorticoid deficiencies –Etc.

7. Cytochrome P450 System Drug Metabolizing Cholesterol Production Steroids Arachidonic Acid Vit D., Etc.

8. Cytochrome P450 Cont: Production of Carcinogens from Procarcinogens –Excessive detox---be careful! Oxidases or Monooxygenases –Increase solubility Cytochrome P450 needs electrons for energy –On the ER the donating protein is NADPH cytochrome P450 reductase –Ferredoxin (adrenodoxin in adrenals) is a donor of electrons in the mitochondria

9. Cytochrome P450 Cont: Non-invasive markers for measuring P450 enzymes –Caffeine (For example) Rate of demethylation –Genetic Profiling (E-sensor)

10. Genetic Polymorphisms

11. Cytochrome P450 Cont:

12. Cytochrome P450 System

13. FUTURE RESEARCH Drug-Drug Interactions (Pharmaseutical Companies) Drug-Botanical Interactions (Not yet begun) Drug-Food Interactions (Beginning) –Grapefruit juice inhibits Cytp450-3A4 Botanicals-Foods Interactions (Not yet begun)