Detoxification of amino acid catabolism products in the gut

Mechanisms of intestinal putrefaction

Not all amino acids ingested with food are absorbed in the small intestine. Some of them reach the large intestine, where they become a nutrient medium for resident microflora. Bacterial enzymes trigger decarboxylation and deamination reactions, turning useful molecules into dangerous metabolites.

As a result of this breakdown, a whole spectrum of compounds is formed: biogenic amines, hydrogen sulfide, as well as cyclic structures—phenols, indole, and skatole. These substances have high toxicity to human cells. They are partially absorbed in the lower parts of the intestine, enter the bloodstream, and are directed via the portal vein to the liver for emergency detoxification. The detoxified forms are subsequently excreted by the kidneys.

Tyrosine transformations: cresol and phenol

The amino acid tyrosine loses its side chains under the influence of microbial enzymes. This step-by-step process leads to the formation first of p-cresol, and then of phenol.

Upon entering the liver, these toxins are detoxified via conjugation reactions (binding to polar molecules). There are two main pathways:

1. Sulfation. Proceeds with the participation of the sulfotransferase enzyme. The donor of the sulfate group is the active form of sulfuric acid—PAPS (3'-phosphoadenosine-5'-phosphosulfate). As a result, cresol sulfuric and phenol sulfuric acids are formed.
2. Glucuronidation. The reaction is catalyzed by UDP-glucuronosyltransferase, which uses UDP-glucuronate. The output yields phenol glucuronide and cresol glucuronide.

The ready conjugates are highly water-soluble and easily leave the body with urine. If a sharp spike in the level of these conjugates is observed in the urinalysis, the physician concludes that intestinal putrefaction processes are intensified.

Tryptophan catabolism: indole and skatole

Another target for bacteria is tryptophan. Microorganisms cleave the $\alpha$-amino group and carboxyl group from it while preserving the massive heterocyclic radical.

Tryptophan degradation pathways are divided into two branches:

• Direct cleavage of the side chain leads to the formation of indole (with serine or alanine as byproducts).
• Via the intermediate stage of indoleacetic acid, skatole is synthesized (with the release of carbon dioxide).

Two-stage detoxification of indole

Skatole and indole are pronounced hydrophobic substances. Because of this, the liver cannot immediately attach a polar group to them, so detoxification takes place strictly in two stages.

Stage 1. Microsomal oxidation To create a "platform" for conjugation, the cytochrome P450 enzyme system hydroxylates the molecule. Indole interacts with oxygen with the participation of the NADPH cofactor. As a result, indoxyl is formed.

Stage 2. Conjugation (sulfation) The resulting indoxyl is treated with sulfotransferase. PAPS is used again as a donor. Indoxyl sulfuric acid is formed.

Its potassium (or sodium) salt is called animal indican. Determining the concentration of animal indican in urine is an important clinical tool that allows assessing how effectively the liver is coping with its detoxification function. Oxidation and conjugation of skatole proceed according to a completely analogous scenario (with the formation of skatoxyl and subsequent attachment of sulfate or glucuronic acid).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structure and biochemical role of the PAPS molecule
• Mechanism of the microsomal oxidation system (cytochrome P450)
• Enzymes of conjugation reactions: sulfotransferases and UDP-glucuronosyltransferases
• Formation and toxic action of hydrogen sulfide and biogenic amines in the intestine

Other topics in the section "Detoxification of toxic substances in the liver"

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