GIT 7 - Metabolism of Xenobiotics PDF

DR.Younes GIT MODULE Metabolism of Xenobiotic ♥ Definition Xenobiotic is a compound that is foreign to the body ♥ such as: 1. Drugs 2. Insecticides 3. Carcinogenic chemicals. ♥ How does the body prevent the actions of xen...

DR.Younes GIT MODULE Metabolism of Xenobiotic ♥ Definition Xenobiotic is a compound that is foreign to the body ♥ such as: 1. Drugs 2. Insecticides 3. Carcinogenic chemicals. ♥ How does the body prevent the actions of xenobiotics? a) Redistribution b) Excretion c) Metabolism (the major mechanism for terminating xenobiotics activity) ♥ Site of biotransformation 1. liver, small and large intestine, , lung 2. brain, kidney and others ❧ Liver is considered as metabolic clearing house for endogenous and exogenous substances (xenobiotics) ❧ Intestine is considered as initial site of drug metabolism ♥ Effects of xenobiotics: 1. Cell injury: Xenobiotics bind to DNA, RNA, protien → cell injury. 2. Antibody formation: Xenobiotics alone cannot induce antibody formation, but when combine with some cellular protein it will stimulate antibody production →damage to the cell 3. Carcinogenesis: Xenobiotics can cause DNA damage, impair DNA repair→ mutation and cancer Phases of xenobiotic metabolism 1. Phase 1: ✦ Hydroxylation is the chief reaction involved in phase1 ✦ hydroxylation catalyzed by Mono-oxygenases or cytochrome P450 (CYP) Dr.Ahmed Younes 1 DR.Younes GIT MODULE N.B.: ❧ RH represents a drugs, carcinogens, pollutants and steroids ❧ In certain cases, phase 1 convert xenobiotic from inactive to active compound. In such cases, the original compounds are called prodrugs or procarcinogens ❧ Other reaction occurs in phase 1: oxidation, reduction, hydrolysis. ❧ NADPH+H is involved in reaction of cytochrome P450 2. Phases 2: ✦ It includes conjugation ,acetylation, methylation A. Coniugation 1. Glucuronidation: ⌚ conjugation with glucuronic acid ⌚ Source of glucuronic acid: UDP glucuronic ⌚ Enzyme: gluronyltransferase ⌚ Bilirubin, aniline, benzoic acid, steroids are excreted as glucuronides. 2.Sulfation: ⌚ Conjugation with sulfate ⌚ Source of sulfate: PAPS (active sulfate donor) ⌚ Compound such as alcohols, phenols and steroids are sulfate conjugated ⌚ Tryptophan→ indol → indoxyl → indoxyl sulfate Dr.Ahmed Younes 2 DR.Younes GIT MODULE 3.Conjugation with glutathione. ⌚ Conjugation with glutathione needs glutathione S-transferase enzyme which is present in high concentration in the liver ⌚ If toxic substances were not conjugated to glutathione. they would combine with DNA or RNA leading to cell damage ⌚ Glutathione is an important defense mechanism against toxic compound such as drugs, carcinogens, so when the concentration of glutathione is lowered in tissues, these tissues become more susceptible to injury by various chemicals B. Acetylation: ✦ Reaction with acetyl CoA by acetyl transferase enzyme C. Methylation: ✦ S-adenosyl methionine (SAM) is the active methyl group donor. ✦ This reaction needs methyl transferase enzyme ⌚ The hydroxylated compounds produced in phase 1 are converted by conjugation to polar metabolites which can be easily excreted in urine or stool ⌚ The aim of these two phases is to increase the solubility of xenobiotic → increase their excretion Dr.Ahmed Younes 3 DR.Younes GIT MODULE Dr.Ahmed Younes 4 DR.Younes GIT MODULE Cytochrome P450 ♥ CYP is hemoprotien in nature. ♥ it contains heme group which act a cofactor because its iron can bind with oxygen and transfer electron ♥ Found mostly in liver, intestine, kidney, adrenal cortex. Functions of CYP 1. Phase 1 of xenobiotic metabolism 2. Metabolism of fatty acids and their derivatives 3. Production of steroid hormone 4. Conversions of chemicals to highly active molecules which may produce unwanted cellular damage, death or mutation. 5. Inactivation or activation of therapeutic agents (drugs) ♥ CYP and drug metabolism: ❧ CYP are the major enzymes involved in drug metabolism → 75% of the total metabolism ❧ Most drugs undergo deactivation by CYPs, either directly or by excretion from the body. ❧ Also, many substances are activated by CYPs ❧ Factors affecting this are: genetic polymorphism, age, gender, disease ♥ CYP and drug interaction ❧ Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of CYP or by directly inhibiting the activity of the CYP. ❧ This is a major source of adverse drug interactions. ☹ A classical example includes erythromycin and mevastatin ☹ mevastatin is metabolized CYP. ☹ Erythromycine is CYP inhibitors, and if taken with mevastatin, the levels of mevastatin in blood will be increased ☹ So, these drug interactions → choosing drugs that do not interact with the CYP CYP as carcinogenic agent: ❧ CYP1A-1 is present in the lung and is important for metabolizing polycyclic aromatic hydrocarbons inhaled by smoking converting it into active carcinogen by hydroxylation reactions Dr.Ahmed Younes 5 DR.Younes GIT MODULE Types of CYP 1. Mitochondrial → inactivates O2 2. Microsomal → metabolize xenobiotics CYP families ❧ Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 sub-families, each has wide and some what overlapping substrate specificites CYP nomenclature a) CYPs are designated with the abbreviation CYP, b) followed by an Arabic numeral indicating the gene family, c) a capital letter indicating the subfamily, d) and another numeral for the individual gene e) e.g. CYP1A1 Most species of cytochrome P450 are inducible i.e. their synthesis in the liver is stimulated by xenobiotics Dr.Ahmed Younes 6 DR.Younes GIT MODULE OBESITY ♥ Definition ❧ Obesity is a disorder of body weight regulatory systems characterized by an accumulation of excess body fat due to energy intake is greater than energy expenditure ❧ Energy intake : occurs by eating and drink consumption ❧ Energy expenditure : occurs through the body's metabolism and physi cal activity ♥ Diagnosis of obesity: 1. Body Mass Index (BMI) ⌚ estimates body fat by dividing a person's weight (kg) to their height (m2). ⌚ BMI is the most common way to determine if a person is affected by overweight or obesity. ⌚ For most adults, a) BMI 18.5 to 24.9 kg/m² healthy weight b) BMI 25 to 29.9 kg/m² overweight c) BMI over 30 kg/m² obese Exceptions are athletes who have large amounts of lean muscle mass. Classes Of Obesity BMI Class of obesity 30-35 kg/m² Class I obesity 35 to 40 kg/m². Class II obesity Class II obesity Class III obesity (morbid obesity) Dr.Ahmed Younes 7 DR.Younes GIT MODULE 2. Measuring the waist size ✦ Measuring the waist size with a tape measure is also used to screen for obesity, because this measurement reflects the amount of fat in the central abdominal area of the body. ✦ The presence of excess central fat is associated with an increased risk for morbidity and mortality, independent of the BMI. Gender Normal (low risk) High risk Very high risk Male Below 94 cm 94-102 cm More than 102 cm Female Below 80 cm 80-88 cm More than 88 cm Causes of obesity 1) Lack of energy balance: A lack of energy balance most often causes overweight and obesity. (Energy balance means that energy IN equals energy OUT). 2) An inactive sedentary life. 3) Environmental factors: Lack of sidewalk, oversized food portions, fast foods, and lack of access to healthy foods. 4) Emotional factors: Some people eat more than usual when they are bored, angry or stressed. 5) Genetic as mutation of leptin or leptin receptor 6) Family history. 7) Hormonal disturbances: Hypothyroidism, Cushing syndrome, and polycystic ovarian syndrome. 8) Medicines: Corticosteroids, antidepressant, and anti-convulsion therapy. Dr.Ahmed Younes 8 DR.Younes GIT MODULE Health risk of obesity 1) Asthma 2) obstructive sleep Apnea 3) Osteoarthritis 4) High Blood Pressure. 5) High Cholesterol and atherosclerosis (where fatty deposits narrow your arteries), which can lead to Coronary heart disease and stroke (thromboembolism). 6) Cancers such as esophageal, pancreatic, colorectal, breast, uterine and ovarian. 7) Type 2 Diabetes. 8) Depression and mood disorders. 9) Fatty liver diseases and gall stones 10) Female infertility and pregnancy complications. 11) Metabolic syndrome. Dr.Ahmed Younes 9 DR.Younes GIT MODULE Body weight regulation 1) Leptin (satiety hormone): ✦ Is a protein hormone secreted by white adipose tissue. ✦ Actions: a) Target appetite control system in hypothalamus (anorexigenic). b) Regulate the balance between body's food intake and energy use (expenditure) and inhibit hunger. c) Having obesity results in high levels of leptin (hyperleptinemia). ⌚ This can cause a lack of sensitivity to leptin, a condition known as leptin resistance. 2) Neuropeptide Y: ✦ The most potent orexigenic peptides were found in the brain. ✦ Stimulates food intake with a preferential effect on carbohydrate intake. ✦ Action ❧ Increases motivation to eat and delays satiety by augmenting meal size. 3) Ghrelin (Hunger hormone): ✦ Produce by gastrointestinal cells (stomach) ✦ Increase between mealtimes and decrease when your stomach is full (orexigenic). ✦ Actions: a) Stimulates food intake, exerts adipogenic activity. b) Modulation of gastric acid secretion and motility. c) Modulation of pancreatic secretions (endocrine and exocrine). d) Secretion of growth hormone. Dr.Ahmed Younes 10 DR.Younes GIT MODULE 4) Adiponectin: ✦ Circulating hormone made by white and brown adipose tissue. ✦ Actions: a) Regulate glucose and lipid homeostasis by promoting a strong insulin sensitizing effect, fatty acid oxidation and mitochondrial biogenesis. b) It is has anti-oxidative and anti-inflammatory effects. c) Inhibit cell growth d) induce apoptosis. ✦ People with obesity have decreased levels of adiponectin. ✦ the more body fat someone has, the lower their adiponectin levels are, and vice versa. 5) Visfatin: ✦ One of the prominent adipokines secreted by adipose tissue. ✦ Actions: ❧ Has insulin-like actions, enhancement of cell proliferation, biosynthesis of NAD and hypoglycaemic effect. ⌚ The level of visfatin increases significantly in people with obesity owing to increased BMI Dr.Ahmed Younes 11 DR.Younes GIT MODULE Management and treatment of obesity ⌚ Patient history: weight-loss efforts, physical activity, eating patterns, appetite control, medicines taken, stress levels and family's health history. ⌚ General physical exam: measuring height, checking vital signs, such as heart rate, blood pressure and temperature; listening to heart and lungs; and examining abdomen. ⌚ Calculating BMI and waist circumference: checked at least once a year to assess health risks and what treatments may be right. ⌚ Checking for other health problems: such as high blood pressure, high cholesterol, underactive thyroid, liver problems and diabetes. Treatment ☞ The first treatment goal is usually a modest weight loss — 5% to 10% of your total weight. 1) Dietary changes : a) Reducing calories: ✦ by review a person‘s typical eating and drinking habits and how many calories usually consume and then decide how many calories patient need to take in each day to lose weight (reduce gradually). ✦ A typical amount is ☹ 1,200 to 1,500 calories for women ☹ 1,500 to 1,800 for men. b) Healthier food choices: eat more plant-based foods include: ✦ Fruits, vegetables and whole grains ✦ Fish twice a week. ✦ Lean sources of protein such as beans, lentils and soy and lean meats. ✦ Limit salt and added sugar. ✦ Eat small amounts of desserts, candies, fats and processed foods. ✦ Restricting certain foods as high-carbohydrate or full-fat foods and replacing fat by olive, canola and nut oils. ✦ Eating healthy snacks and healthy balanced three meal that's low in fat and calories. Dr.Ahmed Younes 12 DR.Younes GIT MODULE 2) Exercise and activity ⌚ Getting more physical activity or exercise is an essential part of obesity treatment ⌚ At least 150 minutes a week (as 30 minutes, five days a week) of moderate-intensity physical activity. ⌚ This can help prevent further weight gain or maintain the loss of a modest amount of weight. ⌚ Gradually increase the amount of exercise ⌚ Regular aerobic exercise is the most efficient way to burn calories and shed excess weight. 3) Medication ⌚ Many recommend medications to use in conjunction with other treatments. ⌚ Medications aren‘t the whole answer to weight loss, but they can help tackle it from another angle. ⌚ Common FDA-approved drugs for treating obesity include: A. Orlistat: Reduces absorption of fat from your gut. B. Phentermine: Decreases appetite. It‘s approved for use for three months at a time. C. Benzphetamine and Diethylpropion: Decreases appetite. D. Bupropion-naltrexone: May reduce cravings and food intake. E. Liraglutide: Reduces appetite and slows digestion. F. Cellulose and citric acid: Makes feel full. Dr.Ahmed Younes 13 DR.Younes GIT MODULE 4) Weight loss surgery (bariatric surgery): ⌚ If you have been diagnosed with class III obesity, bariatric surgery may be an option for you. ⌚ Surgery is a severe but highly effective solution to long-term, significant weight loss. ⌚ Bariatric surgery procedures include: A. Gastric sleeve (sleeve gastrectomy). B. Gastric band (LAP band). C. Gastric bypass (Roux-en-Y). D. Duodenal switch Dr.Ahmed Younes 14