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On Hepatic Detoxification: Phase I


SEE http://liveonearth.livejournal.com/772061.html
for how to influence/support phase I and phase II with nutrition

PHASE I RESULTS IN ONE OF FOUR THINGS
1) substance polarized enough to be eliminated renally
2) toxic intermediate, need phase II working well to avoid trouble (can damage DNA, RNA, other proteins, need GSH to protect vs free radical damage)
3) not so toxic metabolite that goes to phase II
4) no change to initial chemical and it goes to phase II

CYP1A1
induced by smoking cigs and eating charbroiled meat
(is this the reason that smokers metabolize caffeine faster?)

CYP1A2
does 12.7% of the work
high levels of activity linked to incr CRC risk
induced by smoking cigs and eating charbroiled meat

SUBSTRATES OF 1A2
many antidepressants
amitriptyline, clomipramine, imipramine(tricyclic antidepressants)
agomelatine
some atypical antipsychotics: clozapine, olanzapine
haloperidol (typical antipsychotic)
caffeine (stimulant)
ropivacaine (local anaesthetic)
theophylline(xanthine, in respiratory diseases)
zolmitriptan (serotonin receptor agonist)
melatonin (antioxidant, sleep-inducer)
tamoxifen (SERM)
erlotinib[8] (Tarceva, a tyrosine kinase inhibitor)
cyclobenzaprine[6] (muscle relaxant, depressant)
estradiol[6] (in hypoestrogenism)
fluvoxamine[6] (SSRI antidepressant)
mexiletine[6] (antiarrhythmic agent)
naproxen[6] (NSAID)
ondansetron[6] (5-HT3 antagonist)
phenacetin[6] (analgesic)
paracetamol[6] (analgesic, antipyretic)
propranolol[6] (beta blocker)
riluzole[6] (in amyotrophic lateral sclerosis)
tacrine[6] (parasympathomimetic)
tizanidine[6] (α-2 adrenergic agonist)
verapamil[6] (calcium channel blocker)
warfarin[6] (anticoagulant)
zileuton[6] (in asthma)

INHIBITORS OF 1A2
Strong:
ciprofloxacin & many other fluoroquinolones(broad-spectrum antibiotics)
fluvoxamine(SSRI antidepressant)
verapamil (calcium channel blocker)
Weak
cimetidine(H2-receptor antagonist)
Unspecified potency:
grapefruit juice (its bitter flavanone naringenin)[9]
amiodarone (antiarrhythmic agent)
interferon (antiviral, antiseptic, antioncogenic)
methoxsalen (in psoriasis)
Mibefradil (calcium channel blocker)

INDUCERS OF 1A2
tobacco
broccoli, brussels sprouts
chargrilled meat
insulin (in diabetes)
Methylcholanthrene (carcinogen)
modafinil (eugeroic)
nafcillin (beta-lactam antibiotic)
beta-Naphthoflavone (chemopreventive)
omeprazole (proton pump inhibitor)

CYP3A4
is 28.8% of the CYP activity
involved in the majority of drug biotransformations
is the most common cytochrome p450 expressed in human liver
present in high concentrations in the tips of the villi in the intestines
regulated by progesterone/estrogen ratio (HOW?)
premenopausal women have 30-40% more 3A4 than post-menopausal women or men
pregnant women have incr levels of 3A4 activity, if on anti-seizure meds may need incr dose
PROCESSES: sertraline/zoloft, simvastatin/zocor, tegretol, sildenafil/viagra, acetomenophen, codeine, cyclosporin, valium, erythromycin, lidocaine, lovastatin, warfarin, HMG-CoA reductase inhibitors, theophylline, digoxin, estrogen, terfenadine, rosiglitazone, donepezil
ketoconazole, quinidine
INHIBITORS: GRAPEFRUIT, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan
INDUCERS: carbamazepine/tegretol, phenytoin, rifampin, St. John’s wort

CYP2C does 18.2% of the work

CYP2C19
~20% of Asians are poor 2C19 metabolizers

CYP2C19 and STENTING
Plavix is the second largest prescription drug in the world
about a third of individuals can’t metabolize Plavix-->at risk if they undergo coronary stenting
current rate:~2 million stents per year
before giving plavix need genotyping of CYP2C19

CYP2D6 processes fluoxetine/prozac and metoprolol/lopressor
About 5-10% of whites are slow 2D6 processors

cimetidine/tagamet binds the heme directly and strongly inhibits 2C9, 2C6 and 1A2 among others
metabolizes donepezil along with 3A4.

2D6 and 2D19 metabolize abotu 25% of all drugs
including many antipsychotics, antiepressants, and narcotis
slow metabolizers achieve higher drug levels with the usual doses

most toxins are lipophilic
to be excreted in the urine they must be made polar and water soluble
this happens in two stages, phase I and phase II
RT Williams first proposed the two stage biotransformation of toxins by the liver in 1947
stage I uses oxygen to make a reactive site on the molecule
stage II conjugates it by adding a water soluble group
he was right

PHASE I
aka the cytochrome p450 mono-oxygenase system
a group of isoenzymes including the cytochrome p450's which are a superfamily of oxidases
processes include: oxidation, reduction, hydrolysis, hydration, dehalogenation
rxns either add or expose a functional group
most chems must continue to phase II

CYTOCHROME P450
a hemoprotein sim to HGB
in its reduced form (Fe3+) it will bind carbon monoxide
this binding causes the complex to maximally absorb light at 450nm
p450 enzymes found mostly in ER and mito of most cells, and most abundant in the liver
enzymes can be induced and inhibited by a variety of drugs, foods, toxins, metabolic conditions, etc
gut microflora can induce or inhibit detox enzymes
pathogenic bacteria produce toxins that enter the circulation

naming: CYP means it's a cytochrome p450: plants have lots more CYP families than humans
the first number is the family: 40% of the aa's in the primary structure are similar, humans have 18 families
capital letter is subfamily, humans have 43 subfamilies
last number is the gene

GRAPEFRUIT
bioflavonoid naringenin
strong inhibitor of CYP3A4
8oz grapefruit juice reduces 3A4 activity by 30%-->12x increase in some drug concentrations

HYPERICUM/SAINT JOHN'S WORT
induces 3A4
decreases processing time for many meds including OCPs

ORTHOTRICYCLEN
substrate of 3A3, 3A4, 3A5, 3A7
suicide inhibitor of 1A2 (destroys the heme)
makes effects of caffeine and coumadin last longer

CIGS AND CHARBROILED MEAT
dramatically induce 1A1 and 1A2
big increase in phase I activity but little or no increase in phase II
this generates toxic intermediates that aren't immediately processed-->DNA damage-->cancer
high levels of 1A2 have been linked to incr risk of CRC

SOURCES
Jinnah lecture notes
Medscape on 2D19 and stenting: http://boards.medscape.com/forums?128@158.xySzaw48IOY@.2a060fa2!comment=1

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