Production of alcohol
- ethanol C2H5OH (principal alcohol in nature) is
produced by alcoholic fermentation of
carbohydrates - grapes ~16% sugar (mainly glucose)
- produced in over-ripe fruits & by enzymes in yeasts
- small amount from fermentation in colon
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ie C6H12O6 + NADH + ATP -> 2C2H5OH + NAD+ + 2CO2
Absorption & transport
- readily absorbed throughout entire GIT, including stomach
- Rate of absorption is affected by concentration
- transported unaltered in bloodstream
- oxidised mainly in liver to acetaldehyde and then acetate
- in liver and peripheral tissues, acetate is subsequently
converted to acetyl CoA & oxidised via TCA cycle energy - distributed throughout total body water with easy entry through
cell membranes (due to lipid solubility) - Most tissues are exposed to the same alcohol concentration as
blood
After one drink - if 10 g alcohol is diluted in ~40 litres body water (av adult)
- reaches peak blood concentration of 0.025 g/100ml
- permitted limit of blood alcohol for driving is 0.05 g/100ml
Metabolism of alcohol:
On average, people can clear ~ _ g ethanol/ hour from blood.
- women less tolerant of alcohol than men because?
- 3 enzyme systems can oxidize ethanol to acetaldehyde
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- smaller livers
- lower total body water
- higher body fat
- less ‘first pass’ metabolism by alcohol dehydrogenase in gastric mucosa
- Alcohol dehydrogenase (ADH) (cytoplasm)
- Microsomal ethanol-oxidising system (MEOS)
(microsomes, smooth ER) - Catalase, in presence of hydrogen peroxide (peroxisomes)
minor route < 2%
- Alcohol dehydrogenase (ADH)
- major route in most people, requires Zn & NAD+
- oxidises many alcohols to corresponding aldehydes
- is saturable
- is the rate limiting enzyme, requires NAD+
- high ADH activity depletes NAD+ and results in
accumulation of NADH with widespread metabolic
consequences - ADH is saturated with substrate at a cellular concentration
of 15-20 mg ethanol/ 100 ml - spill over of ethanol may be metabolised by alternative
routes, mainly via MEOS in liver microsomes
- Microsomal ethanol oxidising
system (MEOS)
Oxidation occurs in microsomes via an electron transport system,
collectively called the microsomal electron transport system
* similar to mitochondrial electron transport
* ATP (and heat) are generated via oxidative phosphorylation
* may explain why conversion to E is less efficient at high alcohol intake
* involves ‘mixed-function oxidase’ enzymes i.e. two substrates are
oxidised simultaneously by molecular O2:
- ethanol is oxidised to acetaldehyde, and
- NADPH is oxidised to NADP+ (i.e. bypasses need for NAD+)
* requires special cytochromes (P-450) which act as intermediate electron
carriers
MEOS is inducible
Chronic high alcohol intake stimulates proliferation of
microsomal membranes & induces synthesis of MEOS
enzymes (P450)
* thus hepatocytes can metabolise high ethanol intake
more effectively -> ‘tolerance’
* tolerant people ingest larger quantities with less
intoxication
MEOS oxidises various compounds, so induction by alcohol can accelerate metabolism of other substances
metabolised by same system e.g. steroids, tranquilisers,
methadone
* if drug is taken with alcohol, alcohol competes & reduces
drug clearance & degradation
-> dangerously hi levels i.e. possible drug overdose
(less tolerant)
* if drug is taken without alcohol, prior induction can
accelerate drug degradation
-> lower circulating levels with reduced drug effect (more tolerant)
Alcohol ‘intolerance’
Occurs in some individuals with moderate alcohol intake
* marked facial flushing, palpitations, tachycardia, muscle weakness
* may depend on acetaldehyde effects, not ethanol per se
* acetaldehyde stimulates catecholamine release from adrenal
medulla & sympathetic NS (ethanol itself is a CNS depressant)
* 5-10% Caucasians but 60-85% Asians, American Indians
* may result in an aversion to alcohol
Clinical effects of alcohol
Brain & CNS:
- depressive & euphoric effect on mental function
- incr heart rate & peripheral vasodilation, feeling of warmth
Clinical effects of alcohol
Diuretic effect
- ethanol inhibits the normal response of hypothalamic osmoreceptors
- decreased output of antidiuretic hormone (ADH) which normally conserves water
- results in failure to reabsorb water in kidney, possible dehydration
Clinical effects of alcohol
Muscle weakness (progressive with increasing intake)
- ethanol inhibits binding of actin & myosin, interferes with contractility
- long term: cellular swelling, fatty infiltration, fibrosis
- cardiomyopathy & congestive heart failure; skeletal muscle atrophy
Clinical effects of alcohol
Increased blood pressure
- similar effect on smooth muscle of arterioles
- short term 2-3 drinks -> acute incr 10 mm Hg
- long term -> hypertension & risk of stroke in heavy drinkers
Consequences of excessive intake
Acute intoxication
* Hangover: excess alcohol in blood from night before; dehydration
* Chronic alcoholism: dependent or addicted
* Alcohol withdrawal syndrome: regular heavy drinker who stops
* Delirium tremens: hi alcohol in blood for weeks or longer followed by
an accident or illness can trigger
* Dehydration, circulatory collapse, hypothermia, injury
- Acetaldehyde toxicity
Both ADH and MEOS routes of ethanol oxidation produce
acetaldehyde, which has adverse metabolic effects
* attaches covalently to protein -> protein adducts eg
impaired enzyme activity
* impedes formation of microtubules (eg ER) in liver
cells and causes development of fibrosis -> initiates
events leading to liver cirrhosis (widespread fibrosis,
necrosis)
- Lactic acidosis
- both ADH & ALDH use NAD+ as a coenzyme, with formation of
NADH - with high intake of alcohol, NADH accumulates -> shifts
dehydrogenase reactions towards reduction
- Increased lipogenesis
- hi NADH inhibits dehydrogenase enzymes in TCA cycle (isocitrate, a-
ketaglutarate DH) - this slows TCA cycle activity acetyl CoA accumulates
-> diverted to FA synthesis - accumulation of citrate stimulates acetyl CoA carboxylase
- rate limiting enzyme for synthesis of FAs from acetyl CoA
- hence lipid accumulates in tissues where ethanol is metabolised resulting in
- fatty liver also fatty myocardium, fatty renal tubules
- Decreased gluconeogenesis
High NADH inhibits conversion of AAs to carbon skeleton
- Increased vit A requirement
high ethanol intake competitively inhibits conversion of retinol to
retinal
High ethanol intake saturates ADH/ RDH so alcohol & retinol
spill over into the MEOS with induction of microsomal enzymes
* MEOS pathway results in synthesis of inactive oxidation products (not retinal)
* this increases the dietary requirement for vitamin A
- Increased thiamin requirement
Acute thiamin deficiency eg binge drinkers who consume large
amt of alcohol and stop eating for 3 or more weeks.
Chronic thiamin deficiency may lead to permanent brain damage.
Characteristics
* peripheral neuropathy, ataxia (jerky walk)
* quiet confusion, nystagmus, loss of recent memory -> reversible if
treat with thiamin (Wernicke’s encephalopathy)
* but if severe, may still be left with extreme loss of recent memory &
irreversible brain lesions (Korsakoff’s Syndrome)
Relatively high incidence of WE in Australia
* thiamin fortification of bread since 1991 as a preventative measure
-> decrease. see Harper et al, 2012 for more
Toxicity of alcohol
Foetal alcohol spectrum disorders (FAS) > 80g/d during
pregnancy
* Typical facial features
- short nose, small eyes, poor formation of mid face
area, low nasal bridge, small head circumference
* Learning, behaviour and growth problems
* Organ abnormalities e.g. heart or kidneys
Liver disease - chronic intake > 40 - 50 g/d
* enlarged fatty liver
-> hepatitis (inflamed, tender)
-> cirrhosis (widespread fibrosis, necrosis)
Alcohol & CHD
Some evidence suggests light
to moderate alcohol
consumption is associated with
reduced risk of multiple CV
outcomes
Possible mechanisms:
* alcohol increases HDL
* alcohol reduces tendency to thrombosis
* Polyphenolics present in red wine have antioxidant properties that may reduce oxidation of LDL
Alcohol and Cancer
Convincing - Mouth, pharynx & larynx, Oesophagus, Colorectum (men), Breast
Probable - Liver, Colorectum (women
What is standard drink
light beer - 425ml
mid strength beer - 375ml
full strength beer - 285ml
regular cider - 285ml
sparkling wine - 100mk
wine - 100ml
fortified wine - 60ml
spirits - 30ml
Assessment of alcohol
- Blood alcohol concentration not useful in role of nutritionists and dietitians
- Serum Gamma glutamyl tranpeptidase (GGT)
- Raised by intake of alcohol. Also raised in liver disease and with other drugs
- Multiple other liver function tests however used in assessment of liver disease –
not specific markers of alcohol intake - Dietary intake methods – limitations greater than usual
