Question

43.Conjugation reactions in liver: mechanisms and biological role. Conjugation of

xenobiotics and hormones.

(please more explanation Im medicine student)

Answer 1

Biotransformation reactions can be classified into Non-synthetic/Phase -1/ Functionalization reactions and Synthetic/Conjugation/Phase-II reactions.

Synthetic/Conjugation/Phase-2 reactions: where an endogenous radical is conjugated to the drug-metabolite is mostly inactive, except for few drugs.

Example: Glucouronide conjucate of morphine and sulfate conjugate of minoxidil are active.

Conjugation reactions that takes place in liver are Glucuronide conjugation, Acetylation, Methylation, Sulfate conjugation, Glycine conjugation, Glutathione conjugation.

These involves conjugation of the drug or its phase 1 metabolites with endogenous substance to form polar highly ionized organic acid, which is then easily excreted in bile or urine.

1.) Glucouronide conjugation : Most of the important synthetic reaction are carried out by group of UDP-glucuronosyl transferases. Compounds are easily conjugated with glucuronic acid which is derived from glucose.

Example of xenobiotic(drugs) likes Aspirin ,Paracetamol, Morphine. Not only these drugs but the endogenous substances like Bilirubin, Steroidal hormones and thyroxine utilizes this pathway.

Mechanism:

The Glucouronide formation happens by 2 steps:

1.) Synthesis of Activated coenzyme UDPGA from UDPG. The co-enzyme acts as the glucuronic acid donor.

2.) The transfer of glucuronyl moiety from UDPGA to substrate(the xenobiotic ) in presence of enzyme UDP-glucuronyl transferase to form the Conjugate.

The xenobiotics with Hydroxyl or Carbonyl functions form the O-Glucouronide. Hydroxyl form ether Glucuronides were carbonyl forms ester Glucuronides.

The xenobiotics with Nitrogen forms N-glucuronides. Sulfur forms thioether Glucuronides.

Certain steriods, hormones can also undergo this process.

2.) Glutathione conjugation:

It has great affinity for electrophilic substrates, which are number of potentially toxic compounds.

Conjugation with glutathione protects tissuses from such reactive moieties and thus tue reaction is important detoxification route.

Example in case of Organophosphates, epoxides this pathway is important for detoxification.

-- Substrate + GSH will form substrate-S-G complex and H+, X- , this is by nucleophilic substitution at electron deficient carbon.

-- where nucleophilic addition at electron deficient double bond. Example- ethacrynic acid.

In simple the substrate (electrophile) combines with (nucleophile) in presence of enzyme Glutathione-S-Transferase to form the Glutathione conjugate.

The hepatotoxicity of paracetamol overdose is due to the depletion/decrease of GSH.

3.) Methylation:

It differs from the general characteristics of Phase 2 reactions, here the metabolites formed are not polar or water soluble, the metabolites formed are greater or partly active than the parent compound.

□ It is lesser importance in metabolism of xenobiotic but it is more important in biosysnthesis (e.g adrenaline, melatonin) and the inactivation of engogeneous amines (e.g Seretonin, histamine and Nor-adrenaline).

Mechanism: happens by two steps.

Step 1) Synthesis of Activated coenzyme SAM (S-adenosyl methionine, the donor of the methyl group from [L-methionine and ATP].

Step 2) Transfer of methyl group from SAM to Substrate in presence of the enzyme methyl transferase (Non microsomal enzyme).

Its important in methylation of certain xenobiotics by COMT(catachol o methyl transferase) example: Levo-dopa,isoprenaline. O-Methylation (example: morphine), N-methylation : norephedrine etc.

Conjugation reactions biological role:

- To convert the metabolites into polar or ionized to render substrate water soluble.

- Active role in detoxification of toxic metabolites or substrates.

- Making substrates to pharmacologically active or to an inactive form.

Thankyou..