Microsomal P450 Flashcards
Therapeutic cose
ideal concentration of a drug in the blood that gives the desired effects (too high-> toxicity, too low-> no desired effet)
Therapeutic dose depends on the rate at which a particular drug is metabolized
Microsomal P450s and Detoxification
Xenobiotics are nonpolar, lipophilic molecules that are easily diffused across skin and gut epithelium. Once absorbed, usually poorly excreted and accumulation in body can be harmful
Detoxification is a process that increase the hydrophilicity of xenobiotics, so that xenobiotics get excreted
It exists in 2 phases Phase 1 (p450 reaction that adds a polar group) Phase 2 (Conjugation reaction that excretes it)
Phase 1 Enzymes =Cytochrome P450 (CYP)
contain the prosthetic group, heme
Absorb light maximally at 450 nm
They are electron transferring proteins
They are a monooxogynease:
RH +O2 +NADPH + H —> ROH +H2o + NADP
Super gene family (1A1, 3A4 (perscription drugs) etc) 57, most are found in the ER membrane and carry out the detoxification of drugs, xenobiotics, and endogenous substrates (steroids, FAs eicosanoids vitamin D and arachidonic Acid)
Heme is essential for P450s, when activated its bound to cys and ready to carry out hydroxylation reactions
found mainly in the liver, lung, and intestinal mucosaHy
Hydroxylation reaction
The substrate binds to the iron in the heme ring, gets reduced, O2 is added (makes a superoxide), another reduction (making peroxide anion), then oygene activated oxygen and H20 get released twith the substrate leaving with an OH
P450 is also an electron transport chainwith NADPH electrons going to NADPH-Cyt P450-Reductase and FAD and FMN to the P450 region which uses those electrons for the hydroxylation reaction
NADPH is generated by the PPP and malic enzyme system
NADPH use a single oxido reductase (CYPOR)
Phase 2 enzymes
Conjugation enzymes: UGT, GST, SULT (that attach a glucose, SG, an Sulfer group)
Phase 2 enzyme UDP glucuronyl Transferase (UGT)
Most common conjugation reaction (especially in steroid and bilirubin
UGT 1 A1- rate limiting step of bilirubin clearance and can be affected by genetic variation and competing substrates
Gilberts syndrome (usually benign), bilirubin levels are high. So if a drug uses A1A then even less bilirubin is metabolized and the drug is not metabolized
Phase 2 Enzyme Glutathione S transferase and sulfotransferases
y-Glu-cys-gly additions
and SULTs add PAPs
Activation (Carcinogenisis)
sometimes P450s may oxygenate a molecule in a way that phase 2 enzymed cant get to and make reactive oxygen species
Regulation of P450 gene expression
XREs are xenobiotic response elements, function as transcriptional enhancers
Drug interactions
Defined as measurable modifications of the action of one drug with a second drug
some drugs alter p450 activity and therefore can potentiate (induction) or inhibit the metabolism of other drugs, and can change half-life
Some antibiotics inhibit CYP 3A4 which metabolizes oral contreception–> unplanned pregnancies
Mechanism-Based inhibition: the p450 metabolizes the drug and and the acivated metabolite binds irreversibly to P450 (suicide inhibitor)
Disease states: cirrhosis decreaases p450 activity (drugs are not eliminated)
Multiple drug therapies: multiple drugs for the same p450
Some bp drugs slow the breakdown of antibiotics and increase the half life and that causes disease
TCDD Dioxin and Cyp 1A1
Dioxin is released in environment. It binds the Ah which upregulates XRE and then causes the XRE to make ROSs
Dietary influences
Grapefruit juices inhibitors of 3A4s
Cruciferous veggies induce 1 A1a
Iron deficiency -> heme
Ribovalvin deficiency
Polymorphisms
people have different alleles for different P450s
people metabolize drugs differently
Poor, intermediate, extensive, ultrarapid metabolizers
2D6 deficiency people can die, prozac causes 2D6 deficiency (prozac and drugs that are metabolized by 2D6 are given at a lower dose)
2C19 Asians are poor metabolizers, plavix is metabolized by 2c19
CYPOR: Ab syndrome, fetal death
acetominophen APAP
alcoholics are susceptible to its liver toxicity because they dont metabolize it well (2E1) deficiency that makes NAPq1
