Question

How do one-electron transfers by biotransformation enzymes differ from two-electron transfers?

Answer 1

ANSWER

The elimination of xenobiotics often depends on their conversion to water-soluble chemicals through biotransformation, catalyzed by multiple enzymes primarily in the liver with contributions from other tissues.

Biotransformation changes the properties of a xenobiotic usually from a lipophilic form (that favors absorption) to a hydrophilic form (favoring excretion in the urine or bile).

The main evolutionary goal of biotransformation is to increase the rate of excretion of xenobiotics or drugs.

Biotransformation can detoxify or bioactivate xenobiotics to more toxic forms that can cause tumorigenicity or other toxicity

Phase I and II Biotransformation

•With the exception of lipid storage sites and the MDR transporter system, organisms have little anatomical defense against lipid soluble toxins.

•Biotransformation is a major additional defense.

•Xenobiotic metabolism enzymes occur in highest concentration in liver, also in lung, small intestine and other sites of entry.

•Most biotransformation occurs in the endoplasmic reticulum (ER)

Enzymes are the catalysts for nearly all biochemical reactions in the body. Without these enzymes, essential biotransformation reactions would take place slowly or not at all, causing major health problems.

Most biotransforming enzymes are high molecular weight proteins, composed of chains of amino acids linked together by peptide bonds. A wide variety of biotransforming enzymes exist. Most enzymes will catalyze the reaction of only a few substrates, meaning that they have high specificity. Specificity is a function of the enzyme's structure and its catalytic sites. While an enzyme may encounter many different chemicals, only those chemicals (substrates) that fit within the enzyme's convoluted structure and spatial arrangement will be locked on and affected. This is sometimes referred to as the "lock and key" relationship.

As shown in Figure 2, when a substrate fits into the enzyme's structure, an enzyme-substrate complex can be formed. This allows the enzyme to react with the substrate with the result that two different products are formed. If the substrate does not fit into the enzyme ("incompatible"), no complex will be formed and thus no reaction can occur.

Figure 2. If the substrate does not fit into the enzyme, no complex will be formed and no reaction will occur.
(Image Source: NLM)

Enzyme Specificity

Enzymes range from having absolute specificity to broad and overlapping specificity. In general, there are three main types of specificity:

1. Absolute — the enzyme will catalyze only one reaction. Examples:
   • Formaldehyde dehydrogenase catalyzes only the reaction for formaldehyde.
   • Acetylcholinesterase biotransforms the neurotransmitting chemical, acetylcholine.
2. Group — the enzyme will act only on molecules that have specific functional groups, such as amino, phosphate, or methyl groups.
   • For example, alcohol dehydrogenase can biotransform several different alcohols, including methanol and ethanol.
3. Linkage — the enzyme will act on a particular type of chemical bond regardless of the rest of the molecular structure.
   • For example, N-oxidation can catalyze a reaction of a nitrogen bond, replacing the nitrogen with oxygen.

Enzyme Naming Convention

The names assigned to enzymes may seem confusing at first. However, except for some of the originally studied enzymes (such as pepsin and trypsin), a convention has been adopted to name enzymes. Enzyme names end in "ase" and usually combine the substrate acted on and the type of reaction catalyzed.

For example, alcohol dehydrogenase is an enzyme that biotransforms alcohols by the removal of a hydrogen. The result is a completely different chemical, an aldehyde or ketone.

The biotransformation of ethyl alcohol to acetaldehyde is depicted in Figure 3.

ADH = alcohol dehydrogenase, a specific catalyzing enzyme

Figure 3. Biotransformation of ethyl alcohol
(Image Source: NLM)

Beneficial or Harmful?

At this point in ToxTutor you likely see that the transformation of a specific xenobiotic can be either beneficial or harmful, and perhaps both depending on the dose and circumstances.

A good example is the biotransformation of acetaminophen (Tylenol^®). When the prescribed doses are taken, the desired therapeutic response is observed with little or no toxicity. However, when excessive doses of acetaminophen are taken, hepatotoxicity can occur. This is because acetaminophen normally undergoes rapid biotransformation with the metabolites quickly eliminated in the urine and feces.

At high doses, the normal level of enzymes may be depleted and the acetaminophen is available to undergo the reaction by an additional biosynthetic pathway, which produces a reactive metabolite that is toxic to the liver. For this reason, a user of Tylenol^® is warned not to take the prescribed dose more frequently than every 4–6 hours and not to consume more than four doses within a 24-hour period.

Biotransforming enzymes, like most other biochemicals, are available in a normal amount and in some situations can be "used up" at a rate that exceeds the body's ability to replenish them. This illustrates the frequently used phrase, the "dose makes the poison."

Figure 4. Generic acetaminophen tablets
(Image Source: iStock Photos, ©)

Biotransformation Reaction Phases

Biotransformation reactions are categorized not only by the nature of their reactions, for example, oxidation, but also by the normal sequence with which they tend to react with a xenobiotic. They are usually classified as Phase I and Phase II reactions.

Phase I reactions are generally reactions which modify the chemical by adding a functional structure. This allows the substance to "fit" into a second, or Phase II enzyme, so that it can become conjugated (joined together) with another substance.

Phase II reactions consist of those enzymatic reactions that conjugate the modified xenobiotic with another substance. The conjugated products are larger molecules than the substrate and generally polar in nature (water soluble). Thus, they can be readily excreted from the body. Conjugated compounds also have poor ability to cross cell membranes.

In some cases, the xenobiotic already has a functional group that can be conjugated and the xenobiotic can be biotransformed by a Phase II reaction without going through a Phase I reaction.

For example, phenol can be directly conjugated into a metabolite that can then be excreted. The biotransformation of benzene requires both Phase I and Phase II reactions. As illustrated in Figure 5, benzene is biotransformed initially to phenol by a Phase I reaction (oxidation). Phenol has a structure including a functional hydroxyl group that is then conjugated by a Phase II reaction (sulfation) to phenyl sulfate.