NUTR*4510 Toxicology, Nutrition & Food PDF

NUTR*4510 Toxicology, Nutrition & Food Unit 6: Acetaminophen Toxicity and Nutritional Status  Before we focus on Acetaminophen as our main example….Let’s discuss the concept of dietary components interacting with pharmaceutical drugs A common example: Naringin in grapefruit juice...

NUTR*4510 Toxicology, Nutrition & Food Unit 6: Acetaminophen Toxicity and Nutritional Status  Before we focus on Acetaminophen as our main example….Let’s discuss the concept of dietary components interacting with pharmaceutical drugs A common example: Naringin in grapefruit juice and MANY drugs  Food – Drug Interaction: Naringin and Many Drugs Naringin is a phenolic compound (flavonoid) found in grapefruit juice (and other citrus fruits). Interferes with the metabolism and function of MANY drugs. Inhibits CYP3A4 activity → the CYP responsible for ~50% of all drug metabolism E.g. Statin drugs: HMG-CoA reductase inhibitors, the rate limiting enzyme in cholesterol biosynthesis → used to lower blood cholesterol CYP3A4 Not enough drug reaches the target cells Interrupts function of the Organic Anion Transporting Peptide (OATP) family of transporters, that are responsible for the transport of drugs from the blood into cells. If drugs cannot react the target cell they are not effective. Result = ↓ drug bioavailability E.g. Allegra (fexofenadine) for treating allergies  The Grapefruit Effect: Interactions (Inhibition) of Common Drugs Strong Interaction Moderate Weak Interaction Interaction Mevacor & Zocor Lipitor (statin) Allegra (allergy drug) (statin) Valium (sedative) Oncovin & Velban Viagra (erectile (antitumor drugs) dysfunction) Halfan (antimalarial) Cardene & Plendl Zoloft (calcium channel (antidepressant) blockers) BuSpar (antianxiety Prilosec (antacid) drug) Robitussin (cough suppressant) Examples of drugs that have been shown to interact with Naringin Result(s): depends on the mechanism of action (i.e., involving CYP3A4 or OATPs) → adverse side effects of the drug → ineffective drug (and the underlying problem still exists) AREA OF RESEARCH & CONCERN → phenolic compound health effects and high dose purified supplements Center for Food-Drug Interaction Research and Education, University of Florida  Food – Drug Interaction: Seafood and Anti-thyroid Medication Seafood: naturally rich in iodine Anti-thyroids: reduce the physiological production of thyroid hormones T4 and T3 Impair the absorption of iodine in the stomach Used to treat hyperthyroidism (overactive thyroid and high production of thyroxine (T4) Higher dietary intakes of iodine requires a higher dosage of anti-thyroid medication, which can increase the risk of drug side effects (e.g., hives, liver disease, nausea) https://www.todaysgeriatricmedicine.com/archive/101308pe.shtml  Food – Drug Interaction: Potassium (high in bananas) & ACE Inhibitors Bananas: naturally abundant in potassium Angiotensin-converting-enzyme (ACE) inhibitors are a class of medication used to lower blood pressure and prevent heart failure by relaxing arteries. → Downstream suppression of aldosterone causes potassium retention This diet-drug combination causes accumulation of potassium (hyperkalemia) which can stimulate cardiac arrhythmias https://www.thedailymeal.com/healthy-eating/foods-and-pharmaceuticals-don-t-mix-0 Hyperkalemia is a condition in which you have high blood potassium levels (greater than 5.5 mmol/L). Blood potassium level above 6.5 mmol/L can cause heart complications that require immediate medical attention. You may not have any symptoms, or they may be easy to dismiss (as being caused by something else). Severe symptoms may cause muscle weakness or affect your heart. Treatment includes a low-potassium diet, medications that lower your potassium levels and, in severe cases, dialysis.  Food – Drug Interaction: Vitamin K and Anticoagulant Drugs (i.e., Blood Thinners) Vitamin K = Phylloquinone (plant form → leafy green vegetables like kale, spinach, broccoli brussels sprouts) = Menaquinone (form in meats/fish + produced by intestinal bacteria) → Coenzyme needed to produce clotting factors (e.g., prothrombin + others) Warfarin: an example of anticoagulant drug that impairs clot formation by preventing production of vitamin K- dependent clotting factors Need anticoagulant drugs (sometimes called blood thinners) to prevent the formation of blood clots, particularly in prevention of strokes, heart attacks, embolisms or post- surgery. High Vitamin K in the diet and/or supplements counteract the benefits of anticoagulant drugs, and therefore, increase clot formation https://www.stoptheclot.org/news/vitamin-k-and-coumadin-what-you-need-to-know/; https://www.hopkinslupus.org/lupus-treatment/common-medications-conditions/anticoagulants/  Food – Drug Interaction: Calcium (high in Milk) & SOME Antibiotics Calcium (in foods or in supplement form) can bind SOME antibiotics and reduce the absorption of the drug if consumed together. Result = Antibiotic bioavailability decreases Insufficient anti-bacterial effects Antibiotics are not created equal Tetracycline and fluoroquinolone bind Ca+2 Penicillin is not affected by Ca+2 https://health.howstuffworks.com/medicine/medication/antibiotics-interact-dairy.htm  Food – Drug Interaction: Caffeine and Anti-Psychotics Clozapine: an anti-psychotic drug used to treat schizophrenia. Caffeine and clozapine are both metabolized by CYP1A2 and when present together, they compete for metabolism by CYP1A2…therefore, caffeine INHIBITS the metabolism of clozapine resulting in reduced effectiveness of the drug and the formation of the bioactive metabolite (N-desmethylclozapine). This scenario increases the formation of nitrenium…has a free electron and spontaneously reacts with other molecules Inducers of CYP1A2 expression can increase the metabolism of clozapine to it’s bioactive metabolite (e.g. PAHs in cigarette smoke or foods)…which can influence the dose required to effectively treat schizophrenia symptoms without side effects Other metabolites (e.g. nitrenium) that damage hepatocytes and cause neutropenia (↓ # of neutrophils, a form of compromised immune function) CYP3A4 CYP1A2 Clozapine-N-oxide Clozapine N-desmethylclozapine (non-active (bioactive metabolite) metabolite) Acetaminophen Metabolism - 4.0 g is the “recommended” maximum daily dose, though controversy exists about the safety of this dose - At 325 mg / pill, 5.0 – 6.0 g = 15 – 20 regular strength Tylenol pills / day → If assume 70 kg adult, 6g of acetaminophen = dose of 85 mg/kg body weight Acetaminophen (Paracetamol) Follow the maximum allowed daily dose from all sources… >445 products in Canada (combined over-the-counter and prescription medications) E.g. not just Tylenol….many cold medications E.g. prescription drugs….Percocet Information from Health Canada Survey (2004-2008) 33% of Canadians misused over-the-counter drugs 75% of consumers and health care professionals consider non-prescription drugs to be “generally, if not completely, safe” Acetaminophen overdose is a leading cause of acute liver failure in Canada and the U.S 4500 hospitalizations in Canada each year 16% of these were reported as accidental or unintentional overdoses In US, 458 deaths from acetaminophen induced liver failure per year (Lee et al., 2004) Acute Liver damage → occur within hours, may have liver damage without knowing it!! Behaviours that commonly lead to accidental overdose include taking: the next dose too soon more than the recommended dose at a time many people underestimate the risk of doing this 2 or more types of medicine at the same time that contain acetaminophen for example, a pain reliever with a cold and flu medicine https://www.canada.ca/en/health-canada/services/drugs-medical-devices/acetaminophen.html Acetaminophen metabolism - Some pharmaceuticals do not require phase I (i.e. CYP) metabolism – already have a functional group vulnerable to conjugation 1. Acetaminophen (a.k.a. Tylenol) is a nucleophile – may be conjugated by a) glucuronidation or b) sulfation and excreted via urine * These processes are saturated at high doses 2. Some of acetaminophen pool is metabolized by CYP (e.g. CYP3A4 and CYP2E1) to a reactive electrophile intermediate, N-acetyl-p- benzoquinoneimine (NAPQI), which attacks protein sulfhydryl (SH) groups, eventually leading to liver cell death More acetaminophen is metabolized by CYP at high doses Highest CYP activity: CYP 3A4 but also metabolized by CYP2E1, 1A2 and 2D6 3. Some NAPQI undergoes glutathione conjugation to a mercapturic acid conjugate (=APAP-mercaptate) and is excreted via urine. FYI - can also measure glucuronide conjugates and sulfate conjugates in the urine0 1a 1b 2 MAIN – CYP2E1 Other CYPs: 3A4; 1A2; 2D6 3 Reactive intermediate Attack s/reacts with Protein SH groups Liver cell death XXX An old study, but ethically we cannot conduct recent studies where we know the outcome causes toxicities or can even be lethal without a strong rationale. “Old data” is not a strong rationale. Acetaminophen Metabolism and Sulfur Amino Acid Deficiency Price and Jallow, 1989 Objective: test the effect of SAA deficient diet on the balance between phase I bioactivation and phase II detoxification during low and high dose acetaminophen metabolism in rats - Diet: AIN76 basal diet (naturally deficient in SAA) supplemented with various amounts of methionine (Met): 0.31 (deficient, lowest amount), 0.62, 0.93, 1.88 mmol/day = dose-response - 1.88 mmol/day SAA = “complete diet”; meets body SAA requirements Methionine Cysteine GSH Proteins SO42- PAPS - Acetaminophen: low (20 mg/kg) and high (400 mg/kg) dose - High dose saturated metabolic capacity Results after low dose acetaminophen: - Dramatic decrease in urinary SO42- WHY? Used to make PAPS and GSH - Decrease in hepatic GSH levels - Compared to the “complete” diet, Met deficiency: - Decreased total clearance of acetaminophen by 60% - Decreased urinary SO42- conjugates by 80% (reflective of decreased sulfation capacity) - Increased urinary glucuronide and mercapturic acid conjugates - Increased hepatic necrosis (i.e. liver cell death) Acetaminophen Metabolism and Sulfur Amino Acid Deficiency Price and Jallow, 1989 Met deficiency decreased urinary SO4 2- conjugates 1.88 mmol/day Met - SAA are in limited quantity within the total AA pool, therefore, their degradation decreases, which decreases SO42- pool Met deficiency decreased hepatic GSH Days post Acetaminophen exposure - GSH is an essential intracellular reducing agent, so it is maintained at a certain level despite 1.88 mmol/day Met decreased SAA status…needed for conjugation with ROS and for glutathione conjugation (phase II) reactions - This is why there is an initial decrease (being USED following acetaminophen exposure) but hepatic GSH levels that quickly plateau * Body will maintain production of GSH at the expense of other sulfur containing structures e.g. PAPS needed for Days post Acetaminophen exposure sulfation reaction  Acetaminophen Metabolism and Sulfur Amino Acid Deficiency High Acetaminophen (“A”) Dose (400 mg/kg) Log Scale SAA deficient (MET 0.31 mmol/day) had High A modestly lower levels of “A” in the blood vs. complete (control group) (remember this is LOG scale!!!) Reflects higher clearance of drug (‘A”) in SAA deficient vs. control…due to increased glucuronidation AND P450 activation Low A Don’t see a large difference between groups because “A” metabolism pathways are saturated Low “A” Dose (20 mg/kg): SAA deficient rats had higher “A” levels in the blood vs. complete Indicates that drug clearance or metabolism was slower in the SAA deficient group → due to decreased sulfation capacity Met deficiency decreased total clearance of acetaminophen (in the low “A” dose) - Due to decreased Sulfation Met deficiency decreased urinary SO 42- conjugates (previous slide) BUT increased i) glucuronide and ii) mercapturic acid conjugates in the urine i. More acetaminophen metabolized via glucuronidation, which does not require SAA ii. More NAPQI metabolized to mercapturic acid conjugates despite decreased GSH availability Price and Jallow, 1989  Acetaminophen metabolism and sulfur amino acid deficiency @ 400 mg/kg “A” dose more SAA deficient rats have liver damage…~90% affected at the “A” dose that causes liver damage in only 50% of control/complete diet rats (see red circle) Cut off for 50% of rats to have liver damage @ high dose “A” when consuming the complete diet ~280 BLUE LINE → the dose of “A” that causes hepatic necrosis in 50% of in SAA deficient rats ~280 mg/kg…much lower than the 400 mg/kg dose observed in control/complete diet-fed rats. A is more dangerous when SAA deficient Met deficiency increased hepatic necrosis (i.e. liver cell death) in a dose-dependent manner 46 h after acetaminophen administration - With low GSH availability, most NAPQI attacks protein SH groups, causing liver cell death Price and Jallow, 1989  Acetaminophen Metabolism and Sulfur Amino Acid Deficiency @ higher doses, CYP2E1 activation increases along with other P450s Try to maintain GSH levels (they will ↓…BUT, Protein SH groups Liver cell death GSH is biologically essential and needed to quench ROS (produced in Phase I) 1. With low SAA availability, more acetaminophen undergoes glucuronidation instead of sulfation for excretion 2. When glucuronidation is saturated (e.g. at high acetaminophen doses), more NAPQI is formed via CYP2E1 metabolism 3. With more NAPQI, more mercapturic acid conjugates are formed via glutathione conjugation; however, low SAA status results in a big NAPQI pool, and O 2- leakage from CYP2E1 metabolism that limits GSH availability 4. High acetaminophen doses will saturate glutathione conjugation overall 5. NAPQI attack protein SH groups, leading to liver cell death  Acetaminophen metabolism and (lots of) alcohol intake at the same time [ ] Alcohol competes to CYP2E1 bind CYP2E1 (CYP2E1) Metabolism of alcohol → acetaldehyde + ROS Still have NAPQI formation because Ace is metabolized by other CYPs Protein SH groups Liver cell death 1. Alcohol (i.e. ethanol) competes with acetaminophen for CYP2E1 binding 2. With more alcohol binding CYP2E1, less acetaminophen is metabolized via CYP2E1 into NAPQI - i.e. alcohol is a competitive inhibitor of acetaminophen 3. Instead, acetaminophen undergoes glucuronidation or sulfation and is excreted (these pathways are available BUT can become saturated at high acetaminophen doses) - i.e. When taken at the same time, alcohol is a remedy for acetaminophen toxicity… but risky!...why?? ROS and ethanol phase I product (acetaldehyde) is also toxic  Acetaminophen metabolism and (lots of) alcohol intake the night before So now it’s the morning after (or noon when you wake up)….what happens? limited capability limited capability [ ] CYP2E1 (CYP2E1) protein stabilization O2- leakage Other CYPs are present BUT CYP2E1 (needs GSH) is the main player Protein SH groups Liver cell death 1. Excess alcohol induces vomiting and diarrhea → produces short term malnutrition (i.e. starvation-like state) - With low carbohydrate and SAA availability, limited acetaminophen undergoes glucuronidation and sulfation 2. Alcohol and ketones stabilize CYP2E1 (by protein stabilization) and are metabolized by CYP2E1 prior to acetaminophen intake 3. With acetaminophen intake, stabilized CYP2E1 metabolizes it to NAPQI 4. With more NAPQI, more mercapturic acid conjugates are formed via glutathione conjugation; however, low SAA availability, big NAPQI pool, and O2- leakage from CYP2E1 metabolism limits GSH availability 5. NAPQI attack protein SH groups, leading to liver cell death Acetaminophen metabolism and STARVATION limited capability limited capability [ ] CYP2E1 (CYP2E1) Other CYPs: 3A4; 1A2; 2D6 - O2 leakage (needs GSH) Protein SH groups Liver cell death 1. With low carbohydrate and SAA availability, limited acetaminophen undergoes glucuronidation and sulfation 2. Increased ketone production stabilize CYP2E1 protein levels - More acetaminophen is available for metabolism via CYP2E1 to NAPQI 3. With more NAPQI, more mercapturic acid conjugates are formed via glutathione conjugation; however, low SAA status, big NAPQI pool, and O 2- leakage from CYP2E1 metabolism limits GSH availability 4. NAPQI attack protein SH groups, leading to more liver cell death Acetaminophen metabolism and sulfur amino acid deficiency 3 concepts summarize the interaction between toxicology and nutrition: 1) Food as a source ("vector") of natural or synthetic toxins (X) 2) Effect of nutritional status on toxin (X) metabolism 3) Effect of toxin (X) exposure on nutritional status ↓ quality of life