xenobiotics

xenobiotics

Q. 1 In metabolism of xenobiotics all of the following reactions occur in phase one except?

 A

Oxidation

 B

Reduction

 C

Conjugation

 D Hydrolysis

Q. 1

In metabolism of xenobiotics all of the following reactions occur in phase one except?

 A

Oxidation

 B

Reduction

 C

Conjugation

 D

Hydrolysis

Ans. C

Explanation:

Conjugation[Ref. K.D.T. 7″/e p. 24, 25, 26]

  • Drugs are not intrinsic cellular constituents. They are xenobiotics.
  • They are eliminated from the body mainly through kidney.
  • Drug metabolism means necessary changes in the drug molecule which are essential .for easy excretion from the body.
  • Drug metabolism usually converts lipophilic chemical compounds into more readily excreted polar / water soluble / ionizable compounds.
  • When the drug turns polar it becomes more soluble in the extracellular fluid and thus more filterable in the renal tubules. The drug also becomes highly ionizable so it is less reabsorbale and hence readily excretable from the kidney.
  • The metabolism occcurs more or less in every tissue but mainly in the liver.

Usually the drug metabolism occurs in two phases –

  • Phase I and
  • Phase II
  • Phase I and phase II reactions are biotransformations of chemicals that occur during drug metabolism.

Phase I reactions

  • Phase I reactions usually preceede phase II reactions though not necessarily. During these reactions, polar molecules are either added or unmasked, which results in more polar metabolites of the original chemicals. These metabolites are more water solube than the original compound.
  • Phase I reactions can lead to either activation or inactivation of the drug.

Phase I reactions are usually of the following types :

  • Oxidation
  • Reduction
  • Hydrolysis
  • Cyclization
  • Decyclization
  • If the metabolites of phase I reactions are sufficiently polar they may be readily excreted at this point.
  • However many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate (Phase H reaction).

Phase II reactions

  • Phase H reactions are usually known as “conjugation reactions”.
  • This involves conjugation with glucuronic acid, sulfonates and glutathione.

The phase II reactions are ?

– Methylation          

– Acetylation

– Glucuronidation

  • The products of conjugation have increased molecular weight and are usually inactive unlike phase I reactions which often produce active metabolites.

Q. 2 All of the following enzymes and their reactions are involved in the metabolism of Xenobiotics, EXCEPT:

 A Cytochrome oxidase

 B

Cytochrome p 450

 C

Methylation

 D

Hydroxylation

Ans. A

Explanation:

Cytochrome oxidase is not mentioned as an enzyme in the metabolism of xenobiotics but Cytochrome P450 and Hydroxylation reactions are involved in Phase-1 metabolic reactions and Methylation forms a part of phase II reactions.

 
Ref: Harpers Biochemistry, 27th Edition, Page 633; Lippincott’s Illustrated Reviews: Pharmacology, 4th Edition, Page 14; Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition, Page 44

Q. 3 In metabolism of xenobiotics all of the following reactions occur in phase one, EXCEPT:

 A

Oxidation

 B

Reduction

 C

Conjugation

 D

Hydrolysis

Ans. C

Explanation:

Xenobiotic is a compound that is foreign to the body.

The principal classes of xenobiotics of medical relevance are drugs, chemical carcinogens, and various compounds that have found their way into our environment by one route or another, such as polychlorinated biphenyls (PCBs) and certain insecticides.

In phase 1, the major reaction involved is hydroxylation, catalyzed mainly by members of a class of enzymes referred to as monooxygenases or cytochrome P450s. Hydroxylation may terminate the action of a drug, though this is not always the case. In addition to hydroxylation, these enzymes catalyze a wide range of reactions, including those involving deamination, dehalogenation, desulfurization, epoxidation, pre oxygenation, and reduction. Reactions involving hydrolysis (eg, catalyzed by esterases) and certain other non-P450-catalyzed reactions also occur in phase 1.
 
In phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
 
Conjugation reaction occurs in phase 2 and not in phase 1.
Ref: Murray R.K. (2011). Chapter 53. Metabolism of Xenobiotics. In D.A. Bender, K.M. Botham, P.A. Weil, P.J. Kennelly, R.K. Murray, V.W. Rodwell (Eds), Harper’s Illustrated Biochemistry, 29e

Q. 4 What is metabolised like xenobiotics

 A

Myoglobin

 B

Bilirubin

 C

Biliverdin

 D

Haemoglobin

Ans. B

Explanation:

B i.e. Bilirubin

Metabolism of xenobiotics in two phases
  –> In phase 1 reactions, xenobiotics are generally converted to more polar, hydroxylated derivatives
–>,In phase 2 reactionq these derivatives are conjugated with molecules such as glucuronic acid, Sulfate or  glutathione.

–> This renders them even more water-soluble, and they are eventually excreted in the urine or bile Ex.- Bilirubin, bile acids, steroids.


Q. 5

Bile salts undergo xenobiotics:

 A

After conjugation with taurine and glycine

 B

After conjugation with lysine

 C

After conjugation with betaglucuronic acid

 D

After conjugation with derived proteins

Ans. C

Explanation:

C i.e. Conjugation with betaglucuronic acid

– Phase I biotransformation reactions include Hydrolysis, Hydroxylation, Reduction, Oxidation, Oxidative Deamination, Dealkaylation and Epioxidation. Mn “High RODE”. Whereas phase II reactions include Glucronidation, Sulfation, Conjugation (with glucronic acid, glutathione, sulfate or aminoacids), Acetylation and Methylation. Mn “5G-SCAM”.

Cytochrome p450 monoxygenase is the main enzyme responsible for activation of xenobiotics (phase I hydroxylation reaction)Q.

Bilirubin is metabolized like xenobiotics; it is conjugated with beta glucronic acid in hepatocytes to convert a nonpolar hydrophobic bilirubin to a polar hydrophilic one which is readily excreted in bileQ.


Q. 6 In metabolism of xenobiotics all of the following reactions occur in phase one except?

 A

Oxidation

 B

Reduction

 C

Conjugation

 D

Hydrolysis

Ans. C

Explanation:

Ans. is ‘c’ i.e., Conjugation


Q. 7

Xenobiotics are metabolized to ‑

 A

Increase water solubility

 B

Increase lipid solubility

 C

Make them nonpolar

 D

None of the above

Ans. A

Explanation:

Ans. is ‘a’ i.e., Increase water solubility

BIOTRANSFORMATION (METABOLISM)

  • Most of the drugs are treated by the body as foreign substances (xenobiotics).
  • Like other foreign substances (xenobiotics), body tries to eliminate drugs by various mechanisms for ridding itself of chemical intruders.
  • Biotransformation means chemical alteration of the drug in the body.

Why drug transformation is necessary ?

  • Kidney plays a pivotal role in terminating the activity of drugs.
  • For renal excretion the drug tends to be polar (lipid insoluble/water soluble) so that it can not diffuse back from tubular lumen and can be excreted.
  • But pharmacologically active organic molecules (drugs) tend to be lipophlic (nonpolar) and remains unionized or only partially ionized at physiological pH.
  • Biotransformation is needed to render nonpolar (lipid soluble) compounds polar (water soluble) so that they are not reabsorbed in the renal tubules and are excreted.

Sites and processes of biotransformation

  • Primary site of drug metabolism is liver, others are – kidney, intestine, lung and plasma.

Biotransformation of drugs may lead to :-

LInactivation

  • Most drugs and their active metabolites are rendered inactive.

Active metabolite from an active drug

  • Many drugs are partially converted to one or more active metabolites.
  • The effects observed are the sumtotal of that due to the parent drug and its active metabolite.

Activation of inactive drugs

  • Few drugs are inactive as such and need conversion in the body to one or more active metabolites.
  • Such a drug is called prodrug.


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