Biotransformation

Front 1

Liver functions (10)

Back 1

1. blood glucose
2. make and eliminate cholesterol
3. make and export VLDL (TG)
4. make bile
5. make and export ketone bodies
6. urea cycle eliminate ammonia
7. make and elimante blood proteins
8. make heme and eliminate bilirubin
9. make and salvage pruine/pruimidine
10. make special moleucels - creatine, sulfate, traurine, niacine

Front 2

Liver detox
process endogenous/xenobiotic (3)
phase I (4) and II (5) reactions

Back 2

(A) process endogenous: to active form

(B) process xenobiotics
1. active
2. inactivate/eliminate
3. turn into toxins/carcinogens

(C) Phase I:
1. reduction
2. oxidatin
3. hydroxylation
4. hydrolysis

(D) phase II
1. conjugation
2. sulfation
3. acetylation
4. methylation
5. glucuronidation

Front 3

cytochrome P450
what is it, type of rx, location

roles (5)

Back 3

1. heme proteins
2. catalyze oxidation of molecules
3. in prokaryotes, all mammalina except RBC and SK MM

Roles
1. steoid hormone production
2. metabolism of FA, PG, LT, retinoids
3. active/inativate therpauetic
4. convert chemical to reactive molecules -> cell death
5. induction/inhibiton of drug-drug interactions

Front 4

general CP450 action
steps in priming cyt p450 for action

Back 4

(A) NADPH + H + O2 + A-H -> NADP + H2O + A-OH

(B) NADPH pass e- to FAD/FMN DH and reduce iron ion of cyt p450 then oxygen bind to modify substrate

(C) monooxygenation, one atom of O2 goes into substrate A.

Front 5

P450 locations in cell and components

Back 5

1. SER
(a) flavoprotein-NADPH-cyt-450-reductage (FAD, FMN)
(b) e- from NADPH, FAD, FMn, cytp450

2. Inner mito membrane)
(a)NADPH-adrenodoxin reductase (FAD)
(b) NADPH -> FAD -> adrenodoxin (2 iron clusters) -> cytop450

Front 6

CytoP450 activate endogenous biomolecules I

Back 6

1. Synthesis of cortisol, aldosterone
(a) CE -> pregnenlone
- CYP11A1, 3 NADPH + O2 steps
- commitment step
- adrneal mito
(b) pregnenolone -> progesterone
- oxidation
- cytosol
(c) progesteron -> DOC
- ER
- Cpt P21
(d) DOC -> ALDOSTERONE
- hydroxylation CYP11B2
- mitochondrial

(e) pregnenoloen/progesterone -> CORTISOL
- CYP17 ER
- CYP11B1 Mit
- zona fasciculata

2. synthesis of sex hormones
(a) 17 a-hydroxypregnenolone/hydroxyprogesterone -> DHEA/androstenedione
- CYP17
- lose acetyl group
(b) DHEA -> testosterone (androgen)
- sex organs
(c) androgen -> estrogen
- CYP19 (many hydrozylation)
- aromatase (aromatization)

Front 7

deficiency in CYP 21A2

Back 7

(a) congential adrenal hyperplasia (CAHs)
(b) insufficient cortisol production
(c) deficieny CYP21A2 to convet 17-a-OH-progesterone to 11-deoxycortisol to cortisol
(d) increase pituitary ACTh -> adrenal hyperplasia, DHEA, androstenedione
(e) virilization in females

Front 8

CytoP450 activate endogenous biomolecules II

Back 8

Oxygenation of PG and vitamin D activation
(1) D3-> 1,25-dihydroxy D3
- CYP27
- activate
(2) LTB4 -> 20 hydroxyLTB4
- CYP4
- less chemotactic

Front 9

CytoP450 oxidize xenobiotics
general (6)

Back 9

(a) Make lipophilic substance more soluble.
(b) in liver (some in intestine)
(c) phase I: oxidation, functioan group added to cytochrome p450
(d) phase II: biosynthetic reactions, small polar endo molecule added to funcation group.

(e) smooth ER, competitionof many substrate adb inducible by best substrate

(f) 3A4: 50% drugs, 2D6: 20%, 2C9,19: 15% , 1A2&2A6&2B6: 15%

Front 10

CytoP450 oxidize xenobiotics activate, inactive/eliminate

Back 10

Terfenadine -> fexofenadine
(a) activated (hydroxylated) by CYP3A4
(b) eyrthromycin/ketoconaole: inhibit of CYP3A4 -> toxic build-up.

acetaminophne
- sulfation & glucuronidation
- inactivate and eliminate

(1) acetomenophen -> NAPQ1
- CYP2E1

(2) NAPQ1 -> nontoxic
- conjugation wtih glutathione

(3) CYP2E1 induced by alcohol

Statins
(1) CYP3A4 liminate
(2) grapefruit juice inhibit CYP3A4 -> statin build up.

Front 11

CytoP450 oxidize xenobiotics
form toxins

Back 11

benzopyrene-> benzopyrene dihydrodiolepozide
- carcinogen by CYP1A

Front 12

cytochrome p450 inhibitor and regulators

Back 12

inhibitor: CO
CYP2E1: ethanol induces
CYP3A4: induce by 21 carbon steroid, carbamazepine, rifampin, SJW
CYP2B2: induced by phenobarbital
CYP3A1: phenobarbital

Front 13

Polymorphism, poor metabolizers

Back 13

decifiency
CYP2D6: debrisoquine, sparteine, amytruptyline, dextromethorphan, codeine

CYP2C19: methytoxin,
CYP2C9 warfarin