METABOLISM \ BIOTRANSFORMATION:

     A. There are whole families of enzymes specialized for
          metabolism of compounds which would otherwise
          reach toxic levels in the body.

          1. the Cytochrome P450 monooxygenase family: Major
               catalysts of drug biotransformation

               a. very ancient enzymes - 3.5 billion years!

               b.  Heme-containing membrane proteins localized
                    in smooth ER of numerous tissues

               c.  Typically oxidize drugs and endogenous
                    hormones through a wide variety of
                    processes

               d. At least 12 families in humans; of these three
                    families, CYP1, CYP2 and CYP3 do most
                    drug biotransformation, CYP3 in particular

          2.  Hydrolytic Enzymes: 
               
               a. Epoxide hydrolase is localized on ER close to
                    cytochrome P450, further metabolizing
                    reactive products of P450

               b. Protease, peptidase enzymes in most tissues,
                    transform polypeptide drugs

          3. Conjugation reactions: Enzymes conjugate drugs
               with glucoronide (glucoronidation) to render them
               water-soluble, hence easily eliminated

               a. Less commonly, drugs are conjugated via
                    sulfation or acetylation

                   SEE TABLE FOR MORE DETAILS:

     B. THE LIVER: A primary site for metabolic conversion
     /detoxification of exogenous and endogenous compounds

          1. Alcohol dehydrogenase - 15% in gut, rest in
                    liver

          2. P450 - concentrated in liver, gut

          3. Common glucuronidation enzymes also
               concentrated in the liver

     C. Metabolism:

          1. often more than one metabolic product

          2. metabolites generally more ionized, hence
               more easily eliminated in urine

          3. SOME metabolites more active/toxic than
               parent compound

     D. Factors affecting drug biotransformation:

          1. Enzyme INDUCTION:

               a. Exposure to P450 substrates (drugs) can
                    increase P450 enzymes many-fold

                    i. Same true for glucuronidation

               b. Common mechanism of drug TOLERANCE
                    and CROSS-TOLERANCE

          2. Enzyme INHIBITION:

               a. Can cause desirable or TOXIC increases in
                    drug levels

               b. Often caused by metabolic drug interactions
                    between two compounds with affinity for the
                    same P450

               c. Some compounds bind tightly to the heme
                    complex in P450 - Cimetidine, Ketoconazole

               d. Some compounds are "suicide inactivators"
                    of P450s, destroying the heme complex -
                    Secobarbital, synthetic steroids

          3.  Individual differences and Genetic Polymorphisms

               a. There are LARGE individual differences in drug
                    biotransformation

               b. These are often due to genetic differences in
                    metabolic enzymes/pathways

                    i. Extensive (rapid) metabolizers

                    ii. Poor (slow) metabolizers

                    iii. Which is worse depends upon whether
                         the drug or the metabolite is toxic!

          4. Disease - especially liver disease, can impair drug
               metabolism

          5. Age - principally P450 activity decreases with age