Katzung Pharmacology chapter 4
synthesis of which endogenous substrates share enzymes associated with metabolism of xenobiotics
steroid hormones
Vitamin D cogeners
bile acids
usual mechanism of phase I reactions
convert drug to more polar metabolite by introducing or unmasking functional group
hallmarks of phase II rxns
combines glucuronic acid, sulfurinc acid, acetic acid, or amino acid with the polar functional group added in phase I
location of subcellular enzymes used in drug transformations
ER
mitochondria
cytosol
lysosomes
nuclear envelope
plasma membrane
what is the rate limiting step in hepatic drug oxidations
P450 heme reduction
the reductase is less abundant than the hemoprotein
general steps of microsomal drug oxidations
1. oxidized (Fe3+) P450 + drug substrate= binary complex
2. NADPH donates electron to P450 reductase (reduces the P450-drug complex)
3. NADPH adds another e- to reductase, reducing O and making an activated O P450-substrate complex
4. transfers the activated O to the drug
sources of other organic compounds that induce CYP1A
tobacco smoke, charred meat, organic pyrolysis products
chemicals that induce CYP3A
dexamethasone
rifampin
mifepristone
phenobarbital
atorvastatin
hyperforin (St. John's Wort)
basic mechanism of induced P450 synthesis
AhR (cytoplasmic receptor) binds with polycyclic aromatic hydrocarbons-> into nucleus-> dimer with Arnt-> activation of reg elements of CYP1A genes
CAR
constitutive adrostane receptor
used for phenobarbital class of inducers for CYP2B6, CYP2C9, CYP3A4
PPARalpha
nuclear receptor highly expressed in liver and kidneys
lipid lowering drugs as ligands
eg- fenofibrate, gemfibrozil
mediates induction of CYP4A
RXR
retinoid X receptor
forms heterodimer with PXR, CAR, and PPARalpha upon their binding their ligand
how does imidizole inhibit P450
bind tightly to P450 heme iron and reduce substrate metabolism thru competitive inhibition
drug ex: cimetidine, ketoconazole
how do macrolide antibiotics inhibit P450
metabolized by CYP3A, metabolites complex the P450 heme iron and render it catalytically inactive
drug conjugates
drugs coupled with endogenous substance (phase II rxn)
polar molecules that are readily excreted and often inactive
mechanisms of SULTs
sulfotransferases
sulfation of substrates using PAPS (3'phosphoadenosine 5'phosphosulfate- sulfur donor)
NATs
cytosolic N-acetyltransferases
use acetyl CoA as cofactor for metabolizing chemicals with aromatic amine or hydrazine
SAMe
S-adenosyl-L-methionine
mediates O, N, and S methylation of drugs/xenobiotics using methyltransferases
what plays a critical role in the regulation of drug conjugations
nutrition because endogenous substrates originate in teh diet
normal mechanism of acetaminophen metabolism
glucuronidation and sulfation (95%) and P450 dependent GSH conjugation (5%)
when does acetaminophen become toxic
when levels saturate the P450 pathway, no hepatic GSH available for conjugation, toxic metabolite accumulates, damages liver
why is GSH not effective antidote for acetaminophen induced hepatotoxicity
doesn't readily cross cell membranes
what factors influence individual variations in drug distribution, metabolism, and elimination
genetic factors, age, sex, liver size, liver function, circadian rhythm, temperature, nutrition, environment (exposure to inducers/inhibitors of drug metabolism)
slow acetylator phenotype
50% blacks/whites in US, more freq in Europeans at high altitudes
higher incidence of drug-induced autoimmune disorders and bicyclic aromatic amine-induced bladder cancer
genetic polymorphisms in UGT are associated with
hyperbirubinemic diseases and impaired drug conjugation/elimination
genetic polymorphisms in GST associated with
significant adverse effects and toxicities of drugs dependent on GSH conjugation pathway
debrisoquin-sparteine oxidation polymorphism
3-10% whites, auto recessive
CYP2D6 oxidations of debrisoquin, etc are impaired
faulty expression of the P450 protein
ultrarapid metabolism
CYP2D6 polymorphism with up to 13 repeat genes in tandem
common in Ethiopians and Saudi Arabians
CYP2C19 polymorphism
stereoselective aromatic 4-hydroxylation of mephenytoin
auto recessive
3-5% caucasians, 18-23% Japanese
poor metabolizers completely lack enzyme activity
CYP2C9 polymorphism
CYP2C9*2- impaired functional rxns with P450 reductase
CYP2C9*3- lowered affinity for many substrates
CYP2C9*3 polymorphism would affect metabolism of which drugs
warfarin, henytoin, losartan, tolbutamide, some NSAIDs
significance of low CYP2A6 activity
smokers with this gene consume less and have lower incidence of lung cancer
examples of enzyme-inducing drugs
sedative-hypnotics
antipsychotics
anticonvulsants
rifampin (anti-TB)
insecticides