Toxicology - Essay Example

1. Using your knowledge of toxin metabolism, explain how tolerance to and dependence on drugs of abuse can develop. Discuss the factors that can have an effect on the degree of tolerance and dependence. Tolerance can be defined as the reduced response to a drug following repeated exposures to the drug. Subsequently, larger doses are required to achieve the same effect. The process of development of drug dependence is influenced by the drugs properties, the physical characteristics of a person, (including genetic predisposition), personality, socio-economic class, and the cultural and social setting. Factors like peer or group pressure, emotional distress, sadness, social alienation, and environmental stress can lead to increased use and dependence (The Merck Manual Of Diagnosis and Therapy.) Me The Biological Basis of Addiction Although personality, social, and genetic factors may be important factors, the pharmacological activation of brain reward systems is largely responsible for producing a drugs potent addictive properties. “Nonpharmacological factors are likely to be important in influencing initial drug use and in determining how rapidly an addiction develops.” (Addiction Science Network, 2000). Neurobiology of pleasure and addiction Pleasure can be described as a “state or feeling of happiness and satisfaction resulting from an experience that one enjoys.” (Tobias E, George BS, 235-251). Pleasure can serve to promote addiction. The process is a complex neurobiological one, which relies on the reward circuitry or limbic activity. These processes involve dopaminergic signalling. Endorphins and endogenous morphinergic mechanisms may also play a role. Addictive drugs are able to act directly on the reward pathways. Reward pathways are linked to the brain’s limbic system. The euphoria induced by drugs enhances the activity of the brain’s pleasure and reward systems. Various species show differences in the rate of development of tolerance and physical dependence. Even in the same animal, tolerance develops to drugs at different rates, which rules out the possibility of an alteration in drug absorption, metabolism, excretion, etc., as a basis for the tolerance. Although tolerance develops to many of the effects of the opiates, miosis appears to be resistant to tolerance development. The pupil may be always sensitive to opiates because of the existence of different types of opiate receptors whereas the drug receptors on the cells of different tissues become less sensitive to the drug at different rates. “The most important point is that tolerance and dependence develop to different effects of drugs at different rates”(NIDA Research Monograph Series 54.) 2(a) Using suitable examples discuss the factors that influence metabolic detoxification and can lead to lethal synthesis. Different factors may induce or inhibit specific detoxification pathways. These include, various dietary or xenobiotic compounds, age and sex of the individual, genetics, and habits like smoking, and disease states (Liska, DJ.) Factors that induce specific detoxification pathways: a. Polycyclic hydrocarbons from cigarette smoke and aryl amines from charbroiled meats induce Cyp1A1 and Cyp1A2 enzymes. b. Glucocorticoids and anti-convulsants induce Cyp3A4 activity. c. Ethanol, acetone, and isoniazid induce Cyp2E1. d. Multi-functional inducers include flavonoid molecules found in fruits and vegetables. Phase II enzymes maybe induced by ellagic acid found in red grape skin, and by compounds found in garlic oil, rosemary, soy, cabbage, and brussels. The multi-functional inducers commonly induce glutathione S-transferase and glucuronyl transferases. e. Some compounds selectively inhibit only one detoxifying activity. Quinidine competitively inhibits Cyp2D6 activity. Cimetidine inhibits all cytochrome-dependent Phase I enzyme activities by binding directly to the heme iron of the cytochrome P450 reactive site. f. Genetic polymorphism refers to the genetic differences in the ability of an individual to metabolise xenobiotics due to the presence of different versions of the gene encoding that activity. A classic example is the Cyp2D6 gene. The Cyp2D6 enzyme detoxifies many narrow spectrum drugs, including antiarrhythmics, antidepressants, and antipsychotic drugs. Some individuals encode an enzyme with a lower activity than others (slow metabolizers). g. Sex and age also affect the type, amount, and activity of the various detoxification enzymes. Premenopausal women generally show more Cyp3A4 activity than men or postmenopausal women. h. Alcoholic disease, fatty liver disease, biliary cirrhosis, and hepatocarcinoma, impairs the normal liver function, leading to lower detoxification activity in general (Liska, DJ.) Lethal synthesis is a special kind of biotoxification process. The classic example is the conversion of the rat poison fluoro-acetic acid to fluorocitric acid, which inhibits a key enzyme in the citric acid cycle known as aconitase (Duffus JH, 2004.) 2(b) Using suitable examples discuss the significance of phase 1 metabolism of xenobiotics. Most xenobiotics are metabolized through Phase I biotransformation. The Phase I detoxification system is mainly composed of the cytochrome P450 supergene family of enzymes. The major P450 enzymes are the Cyp3A4, Cyp1A1, Cyp1A2, Cyp2D6, and the Cyp2C enzymes. They are usually the first enzymatic defence against foreign compounds (Liska, DJ). The P-450 enzyme system can be disrupted by excess amounts of caffeine, alcohol, dioxin, saturated fats, organophosphorus pesticides, paint fumes, sulphonamides, exhaust fumes, barbiturates, pesticides etc. by causing an over activity or induction of this pathway. Consequently, high levels of damaging free radicals will be produced (Cabot S, 2003.) 3(a) Discuss the significance of dose response curves obtained from animal toxicity studies. After a hazard identification, which is the gathering of information from databases and scientific literature regarding the inherent toxicity of a substance, an analysis of the relationship between the dose received and the respective response is conducted. The analysis is in the form of a dose/response curve. This gives an idea of the potential risk we face when exposed to toxicants. Since the studies are controlled in a lab, animal studies provide precise information about the adverse response to a substance. The data gathered from dose-response studies in animals is useful to set standards for human exposure and the amount of chemical residue that is allowed in the environment. This helps to make informed decisions about chemical exposure and gives an idea on how to minimize the risk to human health and the environment (Extension Toxicology Network, 1993.) 3(b) The degree of toxicity in such studies is dependant on the amount of toxicant delivered to the target(s) in the tissues. What factors influence this delivery? Toxicity of a substance is influenced by the speed with which the substance enters the system, how it is taken up, its interaction with various body tissues, and how the liver and other organs change it. The characteristics of a tissue also influence some of the responses. Although the liver performs the majority of detoxification activity, the first contact of the majority of xenobiotics is with the gastrointestinal tract, since most drugs are consumed orally. To tackle this load, the gastrointestinal tract has developed a complex set of physical and biochemical systems. Detoxification enzymes such as Cyp3A4 and the antiporter activities, which are found at the tip of intestine villi provides a physical barrier to exogenous components. If this barrier function of the mucosa is compromised, adequate detoxification will not take place, allowing xenobiotics to transit into the circulation. The microflora in the gastrointestinal tract can also produce compounds that either induce or inhibit detoxification activities. The toxins produced by pathogenic bacteria can enter circulation and increase toxic load. *************************************************************************** References Addiction Science Network (2000). [Online]. [Accessed December 16, 2005] Cabot S (2003). [Online]. [Accessed December 16, 2005] The Liver Detoxification Pathways. Duffus JH (2004). Human biotransformation of chemicals and mechanisms of action. [Online]. [Accessed December 16, 2005] < http://www.link.med.ed.ac.uk/HEW/tox/human.html> Extension Toxicology Network (1993). Dose-Response Relationships In Toxicology. [Online]. [Accessed December 16, 2005] Liska, DJ. The Detoxification Enzyme Systems. NIDA Research Monograph Series 54. Mechanisms of tolerance and dependence. The Merck Manual Of Diagnosis and Therapy. Drug Abuse and dependence. [Online]. [Accessed December 16, 2005] Tobias E, George BS, Neuroendocrinology letters, 2004; 25(4): 235-251. Read More