In general, where do toxins/toxic agent that cells are exposed to come from?
- external
- GI tract e.g. alcohol
- lung
- skin
ultimately all flow into the bloodstream where they get distributed very rapidly throughout the body - in essence to every single cell in the body that has a capillary supply.
How can metabolism affect toxicity?
Depending on which chemical and which organ is involved the metabolism/the normal metabolic function of those tissues will determine how toxic a particular substance will be
How can storage affect toxicity?
- in the longer term storage of toxins can allow them to exert their effects for longer periods
- otherwise how quickly they can be excreted thereby diminishing the length of time they can exert their effects
What are some examples of recreational and medicinal toxins?
- ethanol
- recreational drugs
- tobacco smoke
- cocaine
- heroin
- amphetamine
- therapeutic drugs
- oral contraceptives
- aspirin
- paracetamol
What happens to a xenobiotic in the body that is non-toxic?
Can undergo a number of different reaction steps: phase I reaction possibilities: - hydrolysis - reduction - oxidation --> produces a primary metabolite
Phase II reactions (require further enzyme activity):
- glucuronidation
- sulfation
- methylation
- conjugation
- -> produces secondary metabolite
- eliminated by normal body processes e.g. urine, bile or feces
What happens to a xenobiotic in the body that is toxic?
- the compound itself initially may not have a strong toxic effect but the metabolites it produces can
- changes from the primary product to a more toxic product can occur
- ways that the toxic metabolite is dealt with either allowing the cells that are exposed to these metabolites to be repaired or longer term effects that reduce the cytotoxicity
xenobiotic ^v reactive metabolite v effects on cellular molecules (enzymes, receptors, membranes, DNA) >> molecular and cellular repair v v Toxicity (short- and long-term effects)
For how long has the effect of alcohol on the liver been known?
Quite a long time
Known in ancient India
300 years ago: english physician named ‘schirrous’ liver in those who consume large amounts if ‘spiritious liquors’
Organs (stomach, liver, heart, kidneys, brain) known to change from their normal state to very recognisably different (even macroscopically).
Psychological changes associated with alcoholism
What are the three major types of pathophyisiology changes that occur in the liver because of alcohol?
- fatty liver
- alcoholic hepatitis (hepatitis = general damage to the liver, causes severe inflammation)
- cirrhosis (irreversible damage to liver, remodels into a non-functional tissue that cannot do any of the things that a normal liver can do in terms of metabolism, detoxification etc)
What is feature of alcohol is important in causing this pathophysiology?
- nature/type of alcohol not important
- daily dose of alcohol IS important
What are the widespread organs affected by alcohol?
- skin
- heart
- pancreas
- bowel
- immune system
- female/male reproductive system
- kidneys
- liver
- stomach
- brain
How can chemicals become toxic?
- some act directly - covalent binding
- some metabolised to toxic metabolic by-products
- many form free radicals –> membrane damage
What constitutes 10 gm of ethanol?
- 1 pot of beer
- 1 glass of wine
- 1 shot spirits
What can prolonged use induce?
- changes to mitochondrial/microsomal functions
- up-regulates expression of metabolising enzymes
What causes the pathology in alcohol consumption?
Ethanol may have a small role but it certainly seems to be the metabolites that have the biggest impact on the liver
What are the consequences of chronic alcohol use?
small to moderate consumption
systemic:
- increases insulin sensitivity
- lower risk of diabetes
brain:
- atrophy
- reduce the number of silent infarcts
- decrease the risk of dementia
blood
- increases HDL
- decreases thrombosis
- reduces fibrinogen
- increases fibrinolysis
- reduces artery spasm from stress
- increases coronary blood flow
skeletal
- higher bone mineral density
Effects linked with both small and large consumption
joints
- reduced risk of rheumatoid arthritis
gallbladder
- reduced the risk of developing gallstones
kidney
- reduced risk of developing kidney stones
Large consumption Brain - impaired development - wernicke-korsakoff syndrome -- vision changes -- ataxia -- impaired memory - psychological -- cravings -- irritability -- antisociality -- depression -- anxiety -- panic -- psychosis -- hallucinations -- delusions -- sleep disorders
mouth, trachea and esophagus
- cancer
blood
- anaemia
heart
- alcoholic cardiomyopathy
liver
- cirrhosis
- hepatitis
stomach
- chronic gastritis
pancreas
- pancreatitis
peripheral tissues
- increased risk of type 2 diabetes
What are the major diseases due to chronic alcohol abuse?
Increased incidence of:
- cancer (alcohol NOT a direct carcinogen) of the oesophagus, larynx, breast, liver
- peptic ulcer in the stomach
- abscess in the lung
- tissue remodelling in the liver: fatty liver syndrome, cirrhosis, hepatitis
What are some of the positive effects of moderate alcohol consumption?
Blood vessels: decreases atherosclerosis, decreased AMI
Blood: inhibits platelet aggregation, decreased thrombosis
Gall bladder: decreased risk of stones
Bone: decreased osteoporosis
How is alcohol metabolised?
After ethanol ingestion:
(GIT = stomach and small intestine):
- absorbed directly via GIT –> blood (minutes)
- metabolised –> some gastric mucosa, mostly liver
- excreted unchanged (5-10%) –> air, sweat and urine/amount proportional to blood
What are the metabolic pathways in the metabolism of alcohol?
- cytochrome P450 enzymes (CYP2E1) = microsomal ethanol oxidising system - a member of the cytochrome P450 oxidase system, is involved in the metabolism of xenobiotics in the body - enriched on smooth endoplasmic reticulum (=microsomes) in LIVER cells
- alcohol dehydrogenase (ADH) - cytosol in GASTRIC mucosal epithelial cells and liver cells ( [ADH] women < [ADH] men)
- catalase - in peroxisomes - in liver cells
Chronic alcohol drinkers - metabolise at higher rate: 5-10x up-regulation of P450
What are the final products of all three metabolic pathways?
Acetaldehyde and acetic acid
Acetaldehyde is a very toxic substance compared to alcohol on its own
What are the effects of ethanol oxidation?
- Acetaldehyde produces acute effects of ethanol
- evidence: oral cancers
- genetic variants: varying metabolic efficiency
- Excess of NADH over NAD stimulates lipid biosynthesis
- production of reactive oxygen species (ROS) - CYP2E1 - membrane breakdown, liver cell injury and possibly DNA damage
What are the effects of alcohol on the CNS?
- powerful depressant
- inhibitory control centres depressed - releases excitatory pathways
- cortex (higher order functions; behaviour, decision making) first then the limbic system (emotions, memory: can change personalities)
- cerebellum (motor control)
- lower brain stem (respiration/BP: may stop breathing/become unconscious)
Party syndrome = euphoria, disordered cognitive and motor function. Occurs at 0.020 - 0.030 gm/dl from 1 or 2 drinks - onset is rapid
At what levels do the acute effects of alcohol occur?
- legal intoxication @ 0.05 gm/dl (australia)
- narcosis @ 0.1gm/dl
- coma/fatal respiratory arrest @ 0.3-0.4 gm/dl
- chronic alcohol drinkers - tolerate much more: e.g. 0.7-0.8gm/dl
What are the acute effects of alcohol on the liver?
- fatty liver
- small (microvesicular) lipid droplets in hepatocytes
- reversible
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