Biotransformation Flashcards
what were listed as the 5 “most important” CYP enzymes
CYP2A2 CYP2A6 CYP2D6 CYP2E1 CYP3A4**
what do P450s use to carry out oxidation of substrates
O2 and H+ from NADPH
pseudocholinesterase metabolizes what drug
succinylcholine
depolarizing neuromuscular blocking drug
N-acetyltransferase metabolizes what drugs
Isoniazid (anti-TB)
Hydralazine (anti-HTN)
Caffeine
what type of genetic defects are associated with decreased N-acetyltransferase ability to metabolize drugs
autosomal recessive
what other symptom is associated with N-acetyltransferase deficiency
hepatitis
what CYP enzyme does grapefruit juice inhibit
CYP3A4
CYP3A4 metabolizes what types of drugs (5)
- anti-hypertensives
- immunosuppressants
- anti-depressants
- anti-histamines
- statins
how does allopurinol affect metabolization of Mercaptopurine and what is the result
it inhibits xanthine oxidase which is what metabolizes mercaptopurine (an immunosuppressant in cancer patients) which prolongs duration of the drug and enhances its chemotherapeutic and toxic effects
why does acetaminophen toxicity occur
too much acetaminophen causes hepatic GSH to deplete faster, so toxic metabolites accumulate resulting in hepatotoxicity
polymorphisms in CYP2D6 cause what
insufficient pain relief and increased side effects of codeine
(CYP2D6 is what metabolizes codeine into morphine)
polymorphisms in CYP2C19 cause what
increased risk of serious adverse CV events
CYP2C19 is what metabolizes clopidogrel to the active thiol metabolite form for anti-platelet activity
28/28 allele genotype in the UGT1A1 enzyme causes what disease
Gilbert’s syndrome (60-70% increase in unconjugated bilirubin)
- UGT1A1 conjugates glucoronic acid onto bilirubin for bile excretion
polymorphic UGT1A1 (not the 28/28 allele genotype) disrupts what biotransformational process
the hydrolization of ironotecan into SN-38 which blocks topoisomerase I, causing the termination of DNA replication and cell death (chemotherapy)
polymorphic UGT1A1 (not the 28/28 allele genotype) causes what sx
- neutropenia
- diarrhea
- decreased clearance of SN-38 metabolite
how does the enzyme TPMT affect Thiopurine drugs (immunosuppressants)
blocks 6-MP and 6-TG (thiopurine drugs) which decreases their therapeutic efficacy but also their bone marrow toxicity
- major determinant of thiopurine metabolism and exposure to cytotoxic 6-TGN metabolites and thiopurine-related toxicities
how does a G6PD deficiency cause problems when using the drug Rasburicase
G6PD is the exclusive source of glutathione in RBCs, and glutathione is needed to reduce the H202 formed when Rasburicase converts uric acid into allantoin. A G6PD deficiency with use of Rasburicase causes hemolytic anemia and methemoglobinemia
how does a reduced function polymorphism in the SLCO1B1 gene affect the uptake of statins
SLCO1B1 encodes the transporter OATP1B1 on the sinusoidal membrane of hepatocytes which controls uptake of statins, so the polymorphism decreases uptake of statins
how does the rs4149056 polymorphism of SLCO1B1 affect use of simvastatin
the polymorphism increases systemic exposure of simvastatin which causes simvastatin-induced myopathy
how do statins normally function
reduce serum lipids and prevent cardiovascular events
what is the normal function of CYP2C9
interacts with microsomal P450 oxidoreductase which metabolizes S-warfarin, which targets VKORC1, a key enzyme in the vitamin K recycling process
how do CYP2C92 and CYP2C93 affect metabolism of warfarin
they block interaction of CYP2C9 and microsomal P450 oxidoreductase, decreasing metabolism of warfarin
what symptoms do genetic variants of VKORC1 cause
may lead to bleeding disorders, eg, multiple coagulation factor deficiency type 2A, or warfarin resistance
how does the VKORC1-1639G>A polymorphism of VKORC1 affect sensitivity of warfarin
results in reduced expression of VKORC1 in the liver –> increased sensitivity to warfarin
