Metabolic detoxification pathways

When xenobiotics (e.g. synthetic drugs) are ingested, they are taken care of by various natural metabolic detoxification processes, aiming to decrease their concentration in the body. Other substances, such as those contained in food supplements, can activate or inhibit this mechanism, significantly impacting medicinal drugs’ availability. Based on Liska and al.’s work, the purpose of this article is to provide an overview of these natural detoxification processes in digestive organs.

Intestinal detoxification

In the case of substances orally ingested, the first contact with the body occurs through the digestive tract. Most drugs go through the various stages of enzymatic digestion, then are absorbed in molecular form by the intestinal mucosa. Water-soluble molecules of low molecular weight (e.g. D-glucose) are sometimes absorbed by the oral mucosa. These are then more quickly conveyed to their action sites. In this case, the hepatic pathway is shunted.

The intestinal absorption efficiency depends on several factors: intestinal flora quality, intestinal microvilli integrity, intra-membrane absorption systems efficiency (in and between enterocytes). Intestinal absorption can also be affected by local detoxification processes. Here, two antagonistic systems have been identified: cytochrome P450 (CYP) and transmembrane P-type glycoproteins (P-gp), encoded by Multi Drug Resistance (MDR) genes. P-gp system is also known as anti-Porter system (Fig.1) and is part of ABC transporters (ATP-Binding Cassette) super family.

Figure 1 : Anti-Porter System / CYP 3A4 in the intestine (Liska, 1998)

Anti-Porter system is a pump that extracts xenobiotics outside the cell, to the intestinal lumen, in order to decrease their intra-cellular concentration. This activity is co-regulated by intestinal P450 cytochromes (e.g. CYP3A4) which promote xenobiotics transfer into the blood. Blood xenobiotics are then brought to the liver, through the portal vein.

Hepatic detoxification

Liposoluble substances reaching the liver undergo detoxification in several phases presented in Fig.2.

Figure 2 : Hepatic detoxification pathways (Liska, 1998)

Phase 1: Functionalization

CYPs “functionalize” nonpolar substances by hydroxylating them (adding OH) to make them polar. These oxidase enzymes include an active site consisting of a Sulfur (from cysteine) and Iron Heme which attracts oxygen. Adequate expression of phase 1 enzymes is mandatory for effective detoxification. CYPs are subject to genetic polymorphism; they vary according to age, gender, diet, lifestyle, environment (epigenetics) and possible diseases. These factors generate different detoxification abilities from one individual to another.

MDR genes have been identified in other organs, particularly the liver, suggesting the existence of an anti-Porter system in this organ. Therefore, there is potentially a third phase of detoxification in the liver.

Intermediate compounds

Polar hydroxylated substances are toxic compounds. If they are not taken up by phase 2, they promote the production of free radicals, which provide oxidative stress.

Phase 2: Conjugation

This phase also allows the transformation of activated compounds (-OH) into water-soluble compounds excretable via urine or bile. These reactions are of several types and operate using cofactors provided by food (e.g. Sulfur, Vit B9, vit B12).

Elimination

Elimination of polar conjugate compounds occurs through urine or bile (then stool).

Enzyme modulations and consequences

CYPs inhibition leads to toxins accumulation in the body and toxicity symptoms (Itkonen, 2019), whereas their over-stimulation leads to an increase of reactive intermediates amounts (Liska, 1998).

Phase 2 reactions inhibition or under-activation leads to an accumulation of reactive intermediate compounds in the body. Inhibition can occur in various ways, in particular by reduction of cofactors essential for a phase 1 (e.g. Iron) or 2 (e.g. vit B9, vit B12) enzymes, or by substrate competition for a detoxification enzyme.

Activation and inhibition mechanisms of natural detoxification are increasingly well documented. They constitute a precious database for today and tomorrow food supplements formulation and dosage.

Leslie Colin

References:

DeAnn J. Liska, The Detoxification Enzyme Systems, Alternative Medicine Review; Volume 3; Number 3; 1998.

M.K. Itkonen, A. Tornio, M. Neuvonen, P.J.Neuvonen, M.Niemi, J.T. Backman, Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans. Drug Metabolism and Disposition : the Biological Fate of Chemicals; 01/10/ 2019, 47(4):377-385.