1 metabolism II Flashcards
what is the purpose of phase 2?
-the major increase in water solubility (and this excretability) of xenobiotics occurs after Phase II reactions, which add (conjugate) a large water-soluble group to an existing polar functional group on the molecule
what is glucuronidation?
-the major phase II biotransformation pathway in mammals
-requires enzyme UDP- glucuronosyl transferase (UGT) and cofactor UDP-glucuronic acid
-located on smooth ER membrane (other phase 2 enzymes are located in cytoplasm)
what is sulfation?
-enzyme sulfotransferase (ST) and cofactor PAPS
-located in cytoplasm
what is acetylation?
-enzyme N-acetyltransferase (NAT) and cofactor acetyl coenzyme A
-located in cytoplasm
what is an example of a biotransformation of phenytoin?
an anticonvulsant drug
-involves phase 1 and 2 enzymes
why is glutathione conjugation such an important enzyme?
one of our most important defenses against reactive electrophiles (reactive oxygen species and epoxides)
-4th phase 2 enzyme
what is glutathione conjugation?
enzyme: glutathione S-transferase (GST)
-abundant enzyme, approximately 5% of cytosolic protein in liver cells
cofactor: glutathione (GSH)
-mM concentrations in most cells (very high concentration)
what are reactive oxygen species and epoxides?
what are glutathione conjugates rearranged to ?
glutathione conjugates are rearranged to mercapturic acid and commonly excreted in bile
what is the graph of acetaminophen biotransformation?
why shouldn’t we take tylenol if we have a hangover?
what is the biotransformation summary?
what is biotransformation :) vs :(?
what are the genetic and environmental factors influencing biotransformation?
- enzyme induction and inhibition
- intraspecific differences
- interspecific differences
- sex and age
- diet (nutritional factors)
- disease (underlying pathology)
what is enzyme induction and inhibition?
-CYP enzymes and phase 2 enzymes can all be induced (Increased activity) and inhibited (decrease activity)
-very toxicologically relevant with respect to duration of xenobiotic action and xenobiotic interactions
-depletion of cofactors (ex: glutathione) can also be very important
what is intraspecific differences?
-genetic differences (polymorphisms) in the expression of enzymes
-can result in a subset of the population being “poor metabolizers” or even “rapid metabolizers”
-classic example is alcohol dehydrogenase (ADH) in humans
what are interspecific differences?
-examples: cats are poor glucuronidators (UGT), dogs are poor acetylators (NAT), and pigs are poor sulfators (ST)
what is sex and age?
-sex-specific differences in certain CYP enzymes
-in general very young and old individuals have lower enzyme activities
what is diet?
-certain dietary ingredients can induce or inhibit phase 1 or phase 2 enzymes (ex: grapefruit juice inhibits CYP3A4 in humans)
what is disease?
-impaired liver function can decrease biotransformation of xenobiotics
what is the table of species differences of sleeping time after injection of hexobarbital (a sedative)
what is the table of species differences in glucuronidation and sulphation?
what is the summary of phenytoin biotransformation?
a patient has epilepsy and you prescribe phenytoin daily. apply your knowledge of biotransformation to consider the outcomes of drug therapy in the following scenario
-induction of CYP or UGT
-inhibition of CYP or UGT
-enzyme polymorphism for CYP or UGT
-the patient is a cat
-the patient is very young or very old
-the patient has a liver disease such as hepatitis or cirrhosis
what is the summary of acetaminophen biotransformation?
