Iba transcript 3 Important that you can recognize functional groups and have an idea what metabolic pathway a particular drug is undergoing Oxidation at a Carbon oxidize a carbon that is alpha to heteroatom (N, S, ) you end up with 2 products you form an intermediate that is very unstable and will decompose to form an aldehyde All the other oxidations, you form one product but When you oxidize a Carbon alpha to an O you hydroxylate the carbon intermediate is unstable continuously nonenzymatically decomposes to an alcohol and aldehyde To a nitrogen intermediate is unstable decomposes to amine and an aldehyde Can also oxidize a sulfur you oxidize a carbon the oxygen will substitute for a sulfuer so you end up with a carbonyl , remove sulfur known as oxidative desulfuration sulfur atoms are exceedingly lipid soluble, and oxygen is less lipid soluble than sulfur containing cmpds Can also oxidize at the nitrogen itself hydroxylamine oxidize the nitrogen as a tertiary function end up with a product that’s very polar N-oxide (not a hydroxylamine) 2ndary Nitrogen has a hydroxylamine Tertiary N-oxide, written with an arrow Sulfur oxidation form a sulfoxide Can also happen on phosphorous atom All of these are cytp450 dependent This particular reaction the formation of N-oxide is very actively metabolized by the other mixed function oxidase flavin monooxygenase FMO most people think that its not very active in catalyzing oxidation of carbon atoms, but it will oxidize S,N,and P Major difference between cytp450 and flavin monooxygenase both are mixed function oxidases in ER the major difference between the two is that p450 is inhibited by CO whereas FMO is not FMO is most active in oxidizing heteroatoms, whereas P450 is active at oxidizing Carbon atoms as well as heteroatoms the next reactions Alcohol oxidation by alcohol dehydrogenaseADH product is always an aldehyde very toxic, very reactive so they need to be eliminated oxidized to less toxic by ALDH oxidize aldehydes to acids these are not p450 reactions oxidative enzymes they will not always introduce oxygens into drug molecules sometimes just simply removing hydrogens and electrons from drug substrates what oxidation is don’t necessarily have to introd. O atoms - depends on the enzyme and the substrate good example is ADH one oxygen in the substrate, theres also one oxygen in the product, no additional oxygen , just removal of Hydrogen atom oxidative deamination primary amine to aldehyde and ammonia not so much a drug metabolizing enzyme MAOs terminate the actions of neurotransmitters enzyme whos fxn is mostly associated with physiological mechanisms capable of oxidizing foreign chemicals, drugs and other toxicants Reduction actions phase 1 Reduce nitro drugs to primary amines sequence eof reactions are involved Quinones para quinone, ortho quinone so that the 2 keto groups are next to each other these are very toxic compounds, will form from drugs so the enzyme NQO1 and reduces them to hydroquinones which are less toxic will go back and forth Carbonyl groups in aliphatic molecules reduced to alcohols carbonyl reductase NQO1 the same will also reduce carbonyls Azo double bond N=N Aliphatic hydrocarbons can undergo reductive dehalogenation and the intermediate is always a free radical and that is a toxic reaction, when you remove halogen from Carbon p450 reduces so you don’t have the few instances that p450 will catalyze reduction reaction, so that the halogenation reaction Is catalyzed by p450 and p450 will also reduce nitro groups Cyp450 is largely an oxidation enzyme Hydrolytic reaction o Ester alcohol and acid o Amides amines and acids o Epoxides formed by p450s are very toxic and reactive and the enzyme that detoxifies epoxides epoxide hydrolase forms cmpd with 2 hydroxy grps detoxification reaction P450 can catalyze the reduction of nitro groups and the dehalogenation reactions are exclusively by p450 Unlike the enzymes that catalyze the metabolism of endogenous cmpds, these do not have rigid specificity Phase 2 reactions March 2 a lot of drugs do not require phase 1 before it goes into phase II these phase 2 reactions these are only 3 of the several phase 2 reactions he’ll talk about sequence in previous slide, phase 2 reactions is to enhance the polarity of cmpds some phase 2 reactions that actually the decrease of their products the whole ideais to increase polarity to enhance excretion, but there are some exceptions can be less polar than parent cmpd. the products of phase II can be more toxic or more pharmacologically active than their precursors Recap. About phase 1 reactions. Oxidations do not always involve an O atom to a drug. all dehydrogenases, will remove hydrogens and the product is an oxygenation product without an additional O, of all the oxidative enzymes there are only 2 that are categorized as MFOs 2 enzymes are cytp450 and FMO The enzyme MAO not a mixed function oxidase and not a microsomal enzyme! Pie chart Grp of enzymes that exist in multiple forms case of acetylation at the Nitrogen is an important phase 2 reaction 2 forms that catalyze acetylation at the nitrogen GST multiple forms Sulfur transferase Glucuronidation accounts for at least 45% of all phase 2 metabolism of all drugs Phase II As by name, it refers to the Condensation of 2 products 1 is an endogenous compound with an endogenous compound cofactor is an endogenous compound in most cases, the essence of the conjugation reaction is to enhance the solubility of the product with exceptions Cofactor for p450 reactions is NADPH Cofactor for FMO I NADPH For ADH and ALDH NAD,+ Activated glucose molecule glucoronidation The important thing is to recognize which functional groups undergo which phase II reactions Among the grps that undergo Gsh conjugation is very important in terms of protecting the body against reactive, toxic intermediates includes epoxides, substitute for nitro (displacement rxns), add glutathione across a double bond, replace halogen with glutathione