EtOH

Question 1

where is the Etoh is absorbed

Answer 1

20% absorbed in the stomach and 80% in the intestines

Question 2

what factors effect absorption

Answer 2

concentration and presence of food in the stomach

Question 3

EtOH distribution

Answer 3

distributes from the blood into the total body fluids, witha volume of ditribition to that of total body water

Question 4

factors affecting total body water

Answer 4

women -> lower total volume body of water = higher BAC

age, sex, weight affect phrmacokinetics of etoh

Question 5

methabloism of EtOH - 2 pathways

Answer 5

1. oxidiative (loss of electrons) - CYP2E1, ADH1, an catalase
2. non-oxidaitve pathways

Question 6

EtOH metabolism in the liver and stomach by ADH

Answer 6

90% is metabolized into acetylaldehyde by AHD (cytosolic)

some studies show CNS metabolizes etoh differently, 60% by catalase and 20% of CYPE2E1, remaining by ADH

Question 7

acetlyaldyhyde metabolism

Answer 7

aceylaldyhyde is metabolized by to acetate aldehyde dehydrogenase ALDH

acetate exists the liver

Question 8

EtOH metabolism by CYP2E1

Answer 8

only up to 10% of EtOH at lower concentrations is metabolized by CYP2E1 in the liver –> membrane bound protein

Question 9

EtOH metabolism by catalase

Answer 9

primarily in peroxisomes, catalyzed the conversion of H2O2 to oxygen and water an in the process, oxidizes EtOH to acetaldehyde

-minimal effect on overall metabolism in the liver, but activity may increase with chronic consumption, and may be important for EtOH metabolism in the brain

Question 10

pregnancy effects on Etoh metabolism

Answer 10

only one report - Badger et al 2005

pregnant rats had increased clearance and lower BAC of EtOH compared to non-preg rate, due at least in part to increase activity of maternal gastric ADH and ALDH

repoted that there was a higher BAC in pregant animals compared to virgin famels (Badger et al 2005; traves and lopzed-tejero 1994)

but other found no difference

Question 11

EtOH metabloism in the fetus

Answer 11

ability to metabolize Etoh will vary with development

studies from the human fetus liver show that low hepatic ADH activity in the fetus, and low expression of its osozymes in the frist trimester

ADH activity will increase with age

CYP2E1 can be detected in early 7-9 week gestation , less likely to play a role in the conceptus, especially in produce which have negligibly CYP activity (wells et al 2014)

Question 12

non-oxidaive pathways of metabolism

Answer 12

by fatty acid ethyl esters synthases (can be a biomarker)

reaction with EtOH with phospholipase D – reuslts in phosphatidyl EtOH can disrupt PA formation and alter signaling pathways

Question 13

EtOH diffusion (Ficks laq)

Answer 13

EtOH can transverse bioligcal membranes according to Ficks first law of diffusion though the smame membrane protien channels that permit the passage of water

Question 14

Etoh ditribution in tissues

Answer 14

tissues with greater blood flow –> kidneys, and brain reach equlibrium quicker than thoes tissues with slow bllod flow like muslce

Question 15

EtOH and placenta

Answer 15

EtOH can easliy cross the placenta, so the BAC in the fetus is on a similar level and follows a similar time course as the mother, with a slower rise and fall in aminoitc fluid compared to the blood (brein et al 1983)

Question 16

Mouse EtOH vs. human dose respsonse cruve

Answer 16

concentration-response cruve for mice and humans may be shifted, –. a higher dose is required for a mouse to achieve the same effect in humans

Question 17

lethal dose of EtOH mouse vs. humans

Answer 17

humans 4 g/kg dose = 118 mM (variable depending on study) – legal limit is ~ 12-23 mM

mouse 8 g/kg dose = 190 mM

rat is 9 g/kg is 214 mM

Question 18

factors affecting BAC (human)

Answer 18

type and concnetration of alcoholic beverage, presence of food in the stomach, differences in the expression of EtOH metabolizing enzymes, volume of ditribution, and amoutn of water and fat in the body

Question 19

BAC and total body water (mouse experiment)

Answer 19

correction for total body water in different mouse strains were nearly identical(Faulkner et al., 1990)

Question 20

human gender differences in EtOH metabolism

Answer 20

numerous studies with contradictory results

but – females reported to have a faster elimination rate and therefore achieve a higher BAC but higher BAC is thought to be due to a lower volume of distribution in females

females also been shown to have lover gastric ADH activity (humans, mice and rats) –> this means females will have higher BAC if given intragastrically but if i.p then males had higher BAC levels

Question 21

age differences in mice BAC

Answer 21

age was down to affect BAC, older rats have lower total body water content compared to younger rats (2-3 months)

Question 22

EtOH hapatic and gastric first pass metabolism

Answer 22

1st step to break down eTOh is catalyzed bt ADH In the liver and gastrc mucosa

Question 23

AHD reaction

Answer 23

a hydrogen is removed with coenzyme NAD+ as an electron acceptor

this oxidation reaction accounts for 90% of Etoh metabolism –> also catalyzed by CYP2E1 and catalyze (lower contribution)

Question 24

EtOH concentration contribution fo CYP2E1

Answer 24

only occurs when the concntration is 10 mM or high (km-8-10 mM )

Question 25

CYP2E1 metabolism ROS generation

Answer 25

ethanol binds to the enzyme (step 1). As the first electron is passed to the heme of CYP2E1 and oxygen is bound (step 2), the electron can move and exist on the oxygen, essentially generating superoxide bound to the heme of CYP2E1 (step 3). Occasionally, the superoxide will break down, releasing free superoxide and generating the starting enzyme. If the second electron is added to the enzyme (step 4), then a second form of reduced oxygen is produced that is identical to a heme-bound form of the two-electron–reduced oxygen (i.e., peroxide) (step 5). When this product breaks down, it picks up two hydrogens to generate hydrogen peroxide. The production of these ROS by CYP2E1 is referred to as an “uncoupled reaction” because the oxygen does not end up in the substrate. If the reduced oxygen species remains bound, then the enzyme will transfer one oxygen atom to the substrate and the other atom becomes water, producing an unstable intermediate (i.e., a gem-diol) product that decomposes to acetaldehyde (step 6).

Question 26

acetaldehyde metabolism

Answer 26

rapdily oxidized to acetic acid by aldehyde dehydrogenase (ALDH2) also aldehyde oxidases, xanthine oxidases, CYP2E1

Question 27

EtOH elmination

Answer 27

10% is excreted unchanged (urine, breath, sweat)

rodents have a much higher elimination rate than humans (mice - 600 mg/kg/h, rat ~ 400 mg/kg/h, humans ~95 mg/kg/hr)

Question 28

EtOH metabolism and ROS

Answer 28

generated directly via CYP2E1 catalyzed EtOH metaboilsm or via oxidation of NAPH by NOxs (more seen in the brain)

Question 29

Etoh metabolism and the CNS

Answer 29

A study (zimatkin et al 2006) suggested that EtOH maybe matabolized differently in the CNS –> 60% by catalase, 20 Cyp2E1 and the remaining by cytosolic ADH and others

Question 30

what are the 3 genreal reasons women have higher BACs then men

Answer 30

1. body compoisition, women have lower total body water percentages (55 vs. 68%), etoh distributes in total body water –> higher bac
2. females do not express gastric AHD enzyme (in men this can reduce absoprtion by 30%)
3. liver adh in women is less effiecint

Question 31

• What is the lethal dose in a human and mice

Answer 31

o 190 mM in mice and 80-90 mM in humans