Biology 137 Introduction to Toxicology Fall Which of the following would enhance the excretion of xenobiotic molecules?

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1 1. Which of the following would enhance the excretion of xenobiotic molecules? A) removal of hydroxyl groups and replacement with hydrogen B) increased hydrophobicity of the molecule, which would allow it to diffuse into the kidney tubules C. binding to protein carrier molecules in the plasma for transport to the kidney D) hydrolysis into smaller nonpolar molecules E. increased hydrophilicity 2. In general the process of biotransformation of xenobiotics produces molecules A) that have a longer biological half-life. B) that have a shorter half-life. C) that can be distributed more uniformly in a single fluid compartment. D) that can be utilized as energy sources E) that are more hydrophobic. 3. Biotransforming enzymes A) are unique because, like antibodies, they have specific substrates B) are only found in specific organs and tissues C) only occur in multicellular organisms that must maintain a homeostatic internal environment D) are classified by specificity of substrate E. are unique because they have broad overlapping specificities. 4. The cytochromes P450 enzymes A) take part only in phase I biotransformation reactions. B) take part only in Phase II biotransformation reactions that occur in the microsomes. C) take part in both Phase I and Phase II biotransformation reactions. D) take part in biotransformations with NADH as a cofactor E) are non-microsomal oxidative enzymes. 5. An example of a non-microsomal oxidation is A) oxidative deamination. B) N-dealkylation. C) alcohol dehydrogenation. D) hydrolysis of esters. E) sulfate conjugation. 6. Phase I biotransforming enzymes A) significantly increase the sizes of xenobiotic molecules B) are found associated with membrane bound ribosomes C) are mostly found on smooth endoplasmic reticulum membranes D) are referred to as microsomal enzymes E) both (C) and (D) are correct. 7. In order for the cytochromes P450 enzymes to perform their activities which of the following components are necessary? A) Fe 3+ B) NADPH C) NADH D) monoamine oxidase E) coenzyme UDPGA 8. A functional group that is added or exposed on xenobiotic molecules during Phase I biotransformation is A) glutathione. B) glucuronic acid. C) hydroxyl (OH). D) sulfates (SO 4 ). E) methyl groups. 9. Which of the following biotransforming products is a highly reactive intermediate? A) nitrogen dealkylation B) desulfuration C) nitrogen oxidation D) aryl epoxide E) glutathione conjugate 10. Although methylation is a minor mechanisms of biotransformation, it is of importance because A) it is involved in neutralization of oxidative free radicals. B) it makes molecules extremely polar. C) it makes molecules more lipophilic. D) it is important in heavy metal metabolism. E. Both (C) and (D) are true. 11. Glucuronidation occurs primarily in the where it is readily excreted in the. A) liver, urine B) kidney, urine C) GI tract, bile D) liver, bile E) GI tract, feces 1

2 12. The cofactor,, is necessary for sulfate conjugation. A) NADPH B) NADH C) Uridine diphospho-gluconronic acid (UDPGA D) S- adenosylmethionine E) 3'-phosphoadenosyl-5'-phosphosulfate (PAPS) 13. Epoxides and free radical intermediates are detoxified primarily by conjugation with A) glucuronic acid B) sulfate C) glutathione D) methyl groups E) alkyl groups 14. Which of the following is an important process in bioactivation of toxic compounds? A) epoxidation of aromatic compounds B) free radical formation C) conjugation D) N- hydroxylation E) Both (A) & (B) are important processes. 15. Most bioactivation processes occur A) in Phase I reactions. B) in Phase II reactions. C) during glucuronic acid conjugation. D) by reduction reactions of bacteria in the GI tract. E) Both (A) & (B) are involved equally. 16. Which is not one of the time dependent processes, which comprise the field of toxicokinetics. A) absorption B) elimination C) latent toxicity effects D) distribution E) metabolism/biotransformation 17. Toxicodynamics or Pharmacodynamics is the study of what a toxicant does to the living system A) True B. False 18. With respect to excretion of toxic substances which of the following is the correct order of importance of the three major routes? A) fecal>lung>kidney B) lung>fecal>kidney C) fecal>kidney>lung D) kidney>fecal>lung 19. The figure above shows the time course of elimination of three different doses of a chemical from plasma after intravenous injection. Which of the following statements is not true? A) Compounds described by this kinetics equilibrate rapidly and uniformly between blood and tissues. B) This is a first order process. C) The slope of each line (k el ) represents a different rate constant for each starting concentration. D) Each of the data sets can be described by a monoexponential function E) All of the above are true. 20. The elimination constant, k el, for a toxin was found to be 0.035/min in the plasma of a rabbit. What is the half-life of this toxin in the plasma? A. 35 minutes B) 3.5 minutes C) minutes D) 19.8 minutes E) 1.98 minutes 2

3 21. The apparent volume of distribution (Vd) for a drug given to a patient was found to be 4.5 liters. The actual plasma volume for this individual is 3 liters. Which of the following would account for this discrepancy? A) excretion of the substance in the urine B) biotransformation processes C) distribution of the drug into the interstitial fluid space D) distribution of the drug into the intracellular fluid compartment E) all of the above 22. Which of the following factors would not have any effect of limiting the bioavailability of a toxin at its site of action? A) limited GI absorption B) intestinal first pass effect C) distribution of the toxin into the intracellular compartment D) hepatic first pass effect E) mode of formulation of the drug when given orally 23. The deamination of adenine (A) to form hypoxanthine (H) results in hypoxanthine pairing with cytosine (C) during subsequent DNA replication. The end point mutation that can occur is A) A:T C:G transversion B) A:T C:G transition C) A:T H:C transition D) H:C C:G transition E. A:T G:C transition 24. Homologous recombination is used by cells: A) when their DNA has undergone frame shifts B) in conjunction with base excision repair processes C) when they are exposed to clastogenic agents D) when large DNA deletions occur as a result of single and double strand breaks E) both (C) and (D) are correct 25. Which of the following is not a criterion for designating a chemical as carcinogenic? A) the induction of tumors in at least one species of laboratory test animal B) development of tumors not normally seen C) decreased latency for development of tumors D) increase in the numbers of tumors in individuals E) increased incidence of one or several types of tumors 26. A requirement for the fixation of point mutations is A) misrepair. B) damage to repair enzymes. C) RNA transcription. D) DNA replication. E) excision repair. 27. The greatest number of people exposed to carcinogens through their diet. A) True B) False 28. The P53 gene A) is involved in regulation of the cell cycle. B) when expressed after DNA damage, induces cell cycle arrest. C) when expressed, is associated with DNA repair D) is expressed prior to cells becoming apoptotic. E) All the above are true. 29. During the predifferentiation (preimplantation) stage of development, the primary effect that is observed is/are A) malformations of the nervous system. B) mutation and development of neoplasms in the newborn individual. C) death of the embryo. D) survival of a complete individual if at least one cell survives. E) Both (C) and (D) are possibilities. 30. During the embryonic stage A) teratogens will produce growth retardation. B) teratogens will produce malformations of the CNS. C) organ susceptibility will occur at different times. D) susceptibility for malformations in all organs and organ systems is the greatest. E) All of the above can occur. 3

4 31. At mid gestation A) the placenta has developed into an effective barrier for agents that might be teratogenic to the developing embryo. B) the maternal biotransformation processes are effective in rendering chemicals hydrodophilic so that they do not cross the placenta. C) the fetal liver is capable of biotransformation, which may result in bioactivation of toxins and therefore making them difficult to excrete by the fetus. D) fetal serum proteins are not yet capable of binding xenobiotic compounds. E) None of the above 32. Unscheduled DNA synthesis as a result of exposure to genotoxic agents is an important repair process for the mature oocyte. A) True B) False Fill in the correct answer. 33. Chemicals that induce DNA damage that results in mutations are termed and chemicals that enhance the expression of tumorigenic DNA lesions are termed. 34. During tumorigenesis the processes referred to as conversion and progression result in the development of the characteristics of and that are the hallmarks of malignancy. 35. During embryogenesis specialized cells in the control processes that initiate differentiation into the three germ cell layers. Many of these processes at this time of development are under the control of expression. Short answer. Answer the first two and choose one more from the remaining three questions. 10 points each. 36. List 4 characteristics of first order single compartment elimination kinetics. 4

5 37. The following data was collected in a rabbit to determine the elimination parameters for a renal toxic substance. The data indicate that a simple single compartment model can be used to obtain the elimination constant, k el = /minute. From this information determine the t 1/2 and the concentration of the substance when it is first injected (at t = 0) and at 90 minutes after injection. t (minutes) C (µg/ml plasma) Explain what is meant when tumorigenesis is described as being a multi-step process. 5

6 39. List five types of DNA damage that are produced by genotoxic agents that result in point mutations (base substitution, frame shifts, etc.) and/or cell lethality. 40. An expectant mother is suffering from malnutrition. Identify and describe two mechanisms that could come into play to affect the developing fetus because of her condition. 6

7 41. Extra credit (10 points). Complete this problem only after you have completed the three required questions above. This is an open note problem. If you did not bring your notes there are extras at the front counter. For each of the compounds indicate the Phase I and Phase II reactions that will detoxify the compound. In your reaction scheme indicate the type or reaction that has occurred and the enzyme(s) that are involved in the particular biotransformation. Hint: use the shortest route to get to the end product. 7