B. Incorrect! Compounds are made more polar, to increase their excretion.

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1 Pharmacology - Problem Drill 04: Biotransformation Question No. 1 of 10 Instructions: (1) Read the problem and answer choices carefully, (2) Work the problems on paper as 1. What is biotransformation? Question #01 (A) The metabolic conversion of endogenous and xenobiotic chemicals to more polar, water-soluble compounds. (B) The metabolic conversion of endogenous and xenobiotic chemicals to more non-polar compounds. (C) Biotransformation leads to an increase in the concentration of the original compound. (D) Biotransformation leads to a decrease in the concentration of the original compound, due to storage in the fat tissue of the body. (E) After biotransformation, the modified compound is only excreted via the kidneys. A. Correct! The metabolic conversion of endogenous and xenobiotic chemicals to more polar, water-soluble compounds. Compounds are made more polar, to increase their excretion. Biotransformation leads to a decrease in the concentration of the original compound. Biotransformation leads to a decrease in the concentration of the original compound. Modified compounds can be excreted via the kidneys, and in the feces. Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more polar, water-soluble compounds, which are then more easily excreted from the body in the urine or feces. This group of processes typically involves chemical modification of the original compound (parent compound), reducing its concentration after biotransformation. Biotransformation is often used interchangeably with metabolism. The correct answer is (A).

2 Question No. 2 of 10 Instructions: (1) Read the problem and answer choices carefully, (2) Work the problems on paper as 2. Where is the largest concentration of metabolizing enzymes? Question #02 (A) In the liver, and brain in most species. (B) In the liver. (C) They are present throughout the body in high concentrations. (D) On a cellular level, the nucleus has the highest concentrations. (E) On a cellular level, the nucleolus and the nucleus have the highest concentrations. The majority are located in the liver. B. Correct! The majority are located in the liver. They are present throughout the body, but not in high concentrations. On a cellular level, biotransformation enzymes tend to be located in: the Endoplasmic Reticulum and a soluble fraction of the cytoplasm. On a cellular level, biotransformation enzymes tend to be located in: the Endoplasmic Reticulum and a soluble fraction of the cytoplasm. Biotransformation is performed by a large number of enzymes distributed throughout the body. Most metabolizing enzymes are concentrated in the liver; they are also present in most bodily tissues at some level. On a cellular level, biotransformation enzymes tend to be located in: the Endoplasmic Reticulum and a soluble fraction of the cytoplasm. The correct answer is (B).

3 Question No. 3 of 10 Instructions: (1) Read the problem and answer choices carefully, (2) Work the problems on paper as 3. Which of the following statements about detoxification is correct? Question #03 (A) The parent molecule is made more polar by the addition of ionizable groups, and the molecular weight and size are increased. (B) The parent molecule is made more non-polar by the addition of ionizable groups, and the molecular weight and size are decreased. (C) A consequence of detoxification is an increase in the biological half-life. (D) The host is exposed for a longer duration, to the parent compound. (E) Detoxification leads to the accumulation of the parent compound in the tissues. A. Correct! The parent molecule is made more polar by the addition of ionizable groups, and the molecular weight and size are increased. The parent molecule is made more polar by the addition of ionizable groups, and the molecular weight and size are increased. Detoxification leads to a decrease in the biological half-life. Detoxification leads to a reduced exposure to the parent compound. Accumulation of the compound in the body is avoided. Detoxification is the process by which a xenobiotic is converted to a less toxic form. The parent molecule is transformed into a more polar metabolite, often by the addition of ionizable groups. The molecular weight and size are often increased. Finally, excretion is facilitated; hence, elimination of the compound from the body is enhanced. The consequences of detoxification are: (1) Biological half-life is decreased. (2) Duration of exposure is reduced. (3) Accumulation of the compound in the body is avoided. The correct answer is (A).

4 Question No. 4 of What is a potential issue with the biotransformation of drugs? Question #04 (A) Xenobiotics only undergo one metabolic transformation. (B) Xenobiotics do not necessarily only undergo one metabolic transformation. (C) Only a single metabolite is produced. (D) Metabolism of xenobiotics does not necessarily result in detoxification; sometimes deactivation can occur, which produces a more toxic metabolite. (E) Metabolism of xenobiotics does not necessarily result in detoxification; sometimes bioactivation can occur, which produces less toxic metabolite. Xenobiotics do not necessarily only undergo one metabolic transformation. B. Correct! Xenobiotics do not necessarily only undergo one metabolic transformation. A variety of metabolites are produced, each with different biologic activity. Metabolism of xenobiotics does not necessarily result in detoxification; sometimes bioactivation can occur, which produces a more toxic metabolite. Metabolism of xenobiotics does not necessarily result in detoxification; sometimes bioactivation can occur, which produces a more toxic metabolite. There are potential issues with biotransformation: (1) Xenobiotics do not necessarily only undergo one metabolic transformation, (2) a variety of metabolites are produced, each with different biologic activity, and (3) metabolism of xenobiotics does not necessarily result in detoxification; sometimes bioactivation can occur, which produces a more toxic metabolite. The correct answer is (B).

5 Question No. 5 of Which of the following is not a factor that can influence biotransformation? Question #05 (A) Availability of cofactors. (B) The level of co-substrates. (C) The age of the individual. (D) The height of the individual. (E) Gender. Availability of cofactors does influence biotransformation. The availability of co-substrates does influence the metabolism of drugs. Age does influence biotransformation, particularly with respect to organ function. D. Correct! While age and gender influence biotransformation the height of an individual does not. Gender does influence biotransformation. There are a number of factors that can affect both Phase I and Phase II reactions, including: (1) Availability of cofactors (2) Availability of co-substrates (3) Enzyme expression levels (4) Species differences between metabolic enzymes expression (5) Age (6) Gender The correct answer is (D).

6 Question No. 6 of Which of the following statements about phase I reactions is correct? Question #06 (A) Compounds can undergo a gain or loss of electrons, but the addition of a water molecule is not a phase I reaction. (B) Compounds can undergo a gain or loss of electrons, and be split through the addition of a water molecule. (C) Most reactions are performed in the motchondria. (D) Monooxygenase is an example of a CYP540 enzyme. (E) Cytochrome P540 is named based on its absorption spectrum. During hydrolysis, the molecule is split into 2 parts with the addition of a water molecule. B. Correct! Compounds can undergo a gain or loss of electrons, and be split through the addition of a water molecule. Most reactions are performed in the smooth endoplasmic reticulum. Monooxygenase is an example of a CYP450 enzyme. Cytochrome P450 is the enzyme superfamily involved in the metabolism of drugs. Phase I reactions primarily fall into 3 categories: (1) Hydrolysis, (2) Reduction, and (3) Oxidation, which is the one most commonly involved in the metabolism of xenobiotics. Most oxidation reactions are performed in the smooth endoplasmic reticulum by a group of enzymes, called monooxygenase enzymes, for example, Cytochrome P450 enzymes and Microsomal enzymes. The correct answer is (B).

7 Question No. 7 of Which of the following examples are phase I enzymes involved in the reduction of compounds? Question #07 (A) Carboxylesterases and Acetylcholinesterase. (B) Alcohol dehydrogenase and Aldehyde dehydrogenase. (C) Carbonyl reductases and Glutathione reductase. (D) Carbonyl reductases and Aldehyde dehydrogenase. (E) Epoxide hydrolase. These enzymes perform hydrolysis. These enzymes are involved in the loss of electrons of the parent compound, known as oxidation. C. Correct! Carbonyl reductases and Glutathione reductase, are examples of enzymes which reduce the molecule s state of oxidation. While carbonyl reductase is a reduction enzyme, aldehyde dehydrogenase performs oxidation. This enzyme performs hydrolysis. Reduction is the process whereby a molecule gains electrons, which reduces the molecules state of oxidation. A number of enzymes catalyze reductions, including: Carbonyl reductases, which includes the alcohol dehydrogenases responsible for detoxifying alcohols and ketones. Thioredoxin-dependent enzymes in the liver and kidney that reduce sulfoxides. Glutathione reductase, which recycles the important cellular antioxidant protein glutathione. The correct answer is (C).

8 Question No. 8 of Cytochrome P450. Question #08 (A) Is the most important phase II enzyme, which detoxifies the largest number of xenobiotics. (B) Has a very narrow range of catalytic specificity. (C) Comes from a very small, narrow group of enzymes. (D) Is represented by 60 genes distributed in 18 families, in humans. (E) Is represented by a single gene that is spliced in many ways, in humans. Cytochrome P450 is a Phase I enzyme. Cytochrome P450 importance is due to its broad range catalytic specificity. The CYP450 superfamily is large and diverse. D. Correct! There are 60 CYP450 genes divided into 18 families. Humans have 60 CY450 genes. The most important Phase I enzyme is monooxygenase, which detoxifies the largest number of xenobiotics. This enzyme has the broadest range of catalytic specificity and is located on SER. CYP450 enzyme family is diverse, both between species and within species. Humans: 60 CYP450 genes, divided into 18 families and 43 subfamilies. These enzymes have overlapping substrate specificity; one CYP450 can metabolize many compounds. The greatest concentration of CYP450s is found in the liver, primarily in hepatocytes. The correct answer is (D).

9 Question No. 9 of How are biotransformation phase II reactions classified? Question #09 (A) Phase II reactions are classified by the molecule added during conjugation. (B) Phase II reactions are classified by the molecule added during hydrolysis. (C) They are classified depending on their location in the cell. (D) They are classified based on whether the reaction makes the original compound more or less polar. (E) Based on whether conjugation is involved in the reaction or not. A. Correct! Phase II reactions are classified by the molecule added during conjugation. Phase II reactions are classified by the molecule added during conjugation. Phase II enzymes are located in the same location within cells, the cytosol. The goal of al phase II reactions is the addition of a large highly polar functional group. They all perform conjugation; the classification is based on what is conjugated to the original compound. Phase II reactions: add a large, highly polar functional group in a process, called conjugation that aids the excretion from the body. These enzymes are located in cytosol of cells. Phase II reactions proceed more quickly than Phase I reactions, and Phase I reactions are the rate-limiting step in biotransformation. Phase II reactions are classified by the molecule added during conjugation: Glucuronidation, Sulfation, Methylation, Acetylation, Amino acid conjugation, and Glutathione conjugation. The correct answer is (A).

10 Question No. 10 of Bioactivation. Question #10 (A) Is not performed by a member of the CYP 450 superfamily of enzymes. (B) Is a mechanism of receptor-receptor activation. (C) Leads to the formation of non-harmful intermediates. (D) Leads to the formation of highly reactive metabolites, which are toxic. (E) Of highly reactive intermediates from aflatoxin B1, protect the cells of the liver from damage. Because CYP450 enzymes are a major player in the detoxification of drugs, they will contribute to bioactivation. Bioactivation is a common mechanism for drug-drug interactions. Leads to the formation of harmful intermediates. D. Correct! Cases of metabolism that produce highly reactive metabolites that are toxic are known as bioactivation. For example, CYP3A4 detoxifies aflatoxin B1, but it also produces a highly reactive intermediate that is both hepatotoxic and tumorigenic. The most common mechanisms for drug-drug interactions are: enzyme induction, enzyme inhibition, and production of reactive metabolites. Cases of metabolism that produce highly reactive metabolites that are toxic are known as bioactivation. Typically, this is mediated by Phase I enzymes. For example, CYP3A4 detoxifies aflatoxin B1, but it also produces a highly reactive intermediate that is both hepatotoxic and tumorigenic. The correct answer is (D).