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
typical functional groups used in phase I rxns
OH NH2 SH
hallmarks of phase II rxns
combines glucuronic acid, sulfurinc acid, acetic acid, or amino acid with the polar functional group added in phase I
principal organ of drug metabolism
liver
other organs involved in drug metabolism
GI skin kidneys lungs brain
location of subcellular enzymes used in drug transformations
ER mitochondria cytosol lysosomes nuclear envelope plasma membrane
MFO/monooxygenases
responsible for oxidative drug metabolism require reducing agent (NADPH) and O2
typical MFO rxn in general
one O2 consumed per substrate molecule, 1 O in product and 1 in H2O
NADPH-cytochrome P450 reductase is made of
FMN and FAD
cytochrome P450
hemoprotein terminal oxidase inc with repeat exposure to drug
what is the rate limiting step in hepatic drug oxidations
P450 heme reduction the reductase is less abundant than the hemoprotein
what do microsomal drug oxidations require
P450, P450 reductase, NADPH, O2
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
what is the common feature of drugs oxidized by the p450 system
high lipid solubility
most important forms of liver P450 enzymes
CYP1A2 CYP2A6 CYP2B6 CYP2C9 CYP2D6 CYP2E1 CYP3A4
which P450 enzyme is responsible for over 50% of the Rx drugs metabolized in liver
CYP3A4
how is P450 expression induced
inc rate of synthesis or dec rate of degradation
sources of other organic compounds that induce CYP1A
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
EHs
epoxide hydrolases hydrolyze endobiotic, drug, and xenobiotic epoxides from P450 oxidations
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
2 effective antidotes to acetaminophen overdosage
cysteamine N-acetylcysteine (safer)
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)
individual differences in metabolic rate depend on
the nature of the drug
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
Ziegler's enzyme
falvin monooxygenase polymorphisms with low activity result in fish-odor syndrome
charbroiled foods and cruciferous vegetables induce which enzyme