Reactive Metabolite Response – Part 1

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM

Metabolite Response

Metabolite production is a common occurrence in the bodyMetabolism is a term that is used to describe all chemical reactions involved in maintaining the living state of the cells and the organism. They can be anabolic (building up) or catabolic (breaking down) in nature. A balanced metabolism is critical to good health and metabolite processing. A damaged metabolism can lead to a buildup of unwanted by-products. All substances therefore are capable of being, and are in fact, looked at as a poison in one degree or another. The right dose differentiates a poison from a remedy, and from being toxic to being beneficial. The body can defend itself against small doses of toxins, and they may even be beneficial as they stimulate protective mechanisms. A large onslaught of toxins, or chronic toxic overload (such as a stealth infection, heavy metal accumulation, ingestion of certain medications), can ruin your health.

A metabolite is defined as a product of metabolism. All substance needs to be broken down into smaller pieces as part of the excretion process to rid the body of unwanted by-products. Toxic substances the body receives from daily living include hormone laced food, polluted air, and unclean water. Excessive metabolites are toxic to the body, and if coupled with damaged intrinsic metabolic or detoxification pathways, can be devastating.

The role of metabolites has been under intense study by the pharmaceutical industry for a long time. The normal process of breaking down medications often generates metabolites that have intrinsic chemical reactivity towards the rest of the body. These by-products therefore have the potential to alter biological function at the cellular level and initiate adverse side effects.

While we may be aware of obvious toxins (such as cyanide) and avoid ingesting them, few are on the alert to know that many foreign substances (including medications and nutritional supplements) can become toxic after it passes through the liver. The liver is the primary organ responsible for breaking down chemical substances in our body into metabolic by-products, which can then be excreted via the renal system. Consider the common pain relief medication acetaminophen. When a standard dose of acetaminophen is taken, it is normally metabolized in the liver. When high doses are taken, the glucuronidation and sulfation detoxification pathways in the liver becomes saturated and metabolism relies more on other pathways such as P450-dependent glutathione conjugation. If glutathione cannot regenerate as quickly as glucuronic acid and sulfate, toxicity in the liver can result, particularly for chronic users of high dose acetaminophen. This risk is seldom addressed until a person is in trouble.

Metabolic Variability

The availability of enzymes to perform the metabolic breakdown work, in the liver, can vary greatly between individuals and, as a result, the efficacy of metabolism of different compounds is person specific. Some people can handle great insult to the liver and show no clinical symptoms, while others are not so fortunate. They succumb to the smallest amount of toxic metabolite when generated in the liver. Genetics play a big role , as well as lifestyle, diet, and the volume of medication taken.

Taking certain medications can increase the build up of metabolite byproductsIt is also important to note that the metabolism of chemical substances such as medications does not always lead to toxicity and, in some cases metabolites can be used to our advantage in clinical medicine. For example, codeine is a common pain relief medication. When codeine passes by the liver, it is metabolized to norcodeine, codeine-6-glucuronide, and morphine. The metabolite morphine is the most potent and important in the pain relieving effect of the medication. The enzyme responsible for this chemical breakdown pathway is known to vary greatly among different individuals, which accounts for why some patients notice large effects with small doses because they are extensive metabolizers while others barely notice the effect even with large doses.

Active versus Inert Metabolite

The basic principle of desired drug metabolism is to convert a lipophilic medication or xenobiotic to hydrophilic metabolites so it can be more readily excreted from the body in a chemically inert form rather than accumulating within. In this process of breakdown, metabolites are generated. Unfortunately, not all metabolites are inert. Some are active. The biotransformation of relatively inert metabolite chemicals to highly active and reactive metabolites are commonly referred to as bioactivation. This is usually thought of as the initial event in many chemically induced toxicities.

Considering that the liver is the organ most exposed to a high concentrations of drug after oral administration, it is therefore the organ most vulnerable to damage by medications and drugs.

The body has built in detoxification mechanism in place to convert natural compounds into inert metabolites prior to excretion. Problems come usually when foreign or synesthetic compounds, such as drugs and herbs, are introduced. The body does not have the built in detoxification mechanism to do the job fully and completely. Unwanted metabolite buildup can occur. Some of these metabolite are not inert but active. In most cases, the build up of chemically active metabolites is temporary and the body eventually gets rid of it. In other cases, such as with toxic metal like mercury, it never leaves the body on its own.

Prevention of active metabolite-mediated toxicity is important, especially for those who are weak and fragile. They include those recovering from trauma, chronic disease sufferers, and the aging population as a whole. Those, already with adrenal fatigue, are particularly at risk.

Reactive Metabolites

Chemically active metabolites can cause toxicity either by direct extension of the properties of the mother compound, or are dependent on the pharmacology of the metabolite itself. They are therefore called reactive metabolites. Damage may be widespread or cell-specific. Cell death may be affected by various mechanisms.

DNA reacts with metabolite levels in the bodyWell known groups of reactive metabolites include reactive oxygen species, unstable conjugates, quinone, imine quinone, quinone methide, arene oxides. Reactive metabolites are usually electron deficient molecules called free radicals. They are short lived, but they can be transported from one tissue to another, where biochemical insults occur. They can directly react with proteins causing changes in protein structure. These modified proteins can be damaging to the body. Chemically reactive electrophiles can also react with nucleic acids on the DNA, leading to DNA structure change or gene expression. Changes in DNA can lead to mutagenicity, teratogenicity or ultimately carcinogenicity. Fortunately, the body has an internal system of identifying such reactive metabolites. Once detected, an inflammatory and immune response will be activated to neutralize them. Unfortunately, not all bodies can do this effectively.

While reactive metabolites have been well studied in medications by the pharmaceutical industry, few advances have been made to fully understand the role they play when part of nutritional supplements such as vitamins, glandular, herbs, and hormones used frequently in the adrenal fatigue setting.

Reactive Metabolites in Natural Compounds

Nutritional supplements, while natural, also needs to be broken down and converted to inert metabolite for excretion.

Consider the following:

  • Vitamin C, a commonly consumed vitamin, is metabolized primarily in the liver after absorption through the GI tract. It is oxidized to dehydroascorbate with the formation of semi dehydroascorbate radical. The oxidized form may be reduced back to ascorbate by glutathione (GSH), NADH, and NADPH. The oxidized form is further oxidized to 2,3 diketogulonic acid which in turn is cleaved into oxalic acid and L-threose prior to excretion out of the body. These metabolites may not be well tolerated by the body, especially in those who are weak. Some people feel energized after taking vitamin C because it plays an important role in the synthesis of catecholamines, particularly dopamine and norepinephrine. However, they experience fatigue crashes a short time later possibly as result of metabolic by-products accumulation.
  • Tyrosine, a common amino acid, is converted to a class of compound called catecholamine such as dopa, dopamine, norepinephrine, and epinephrine. Each of these downstream compounds has it own positive and negative properties. Norepinephrine, for example, causes mental alertness to increase, but can also trigger heart palpitation and increase in blood pressure. These downstream compounds each, in turn, go through multiple break-down processes, generating metabolites that can be inert or reactive. Reactive intermediates formed during catecholamine oxidation have been associated with cardiac toxicity where oxidative stress is involved.

Metabolite production from serotonin

  • Serotonin, the feel good chemical and a key neurotransmitter in the gut-brain axis on both terminals of the network, is derived from tryptophan. Melatonin, a commonly used sleep-aid, is the chemical daughter of serotonin. Metabolism is by way of oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative, which is then transported and excreted by the kidneys. Alterations of serotonin metabolism and its metabolites may give rise to gastrointestinal dysfunction because gut microbiome influences the behavioral link to serotonergic neurotransmission.
  • Progesterone, an important female hormone is the chemical precursor of cortisol, androstenedione, and numerous hormones and metabolites. It is primarily metabolized in the liver. Its sedative and calming central nervous system effect is a property of the metabolites acting through GABA receptors rather than progesterone itself. The effect is seen to be both quantitative and qualitative, depending on dosage and delivery system (which elicit different metabolization processes). For example, oral progesterone undergoes successive metabolic steps in the gut involving the microbiome, intestinal wall, and liver. Specific benefits may be expected, from oral administration, on mood and sleep disturbances. On the other hand, vaginally delivered progesterone may induce more predictable endometrial secretory changes without CNS influence.
  • Excessive progesterone and its reactive metabolites can lead to toxicity symptoms including immune suppression, depression, heart palpitation, anxiety, liver pain, sore joints, constipation, dry skin, kidney pains, insulin resistance, high blood sugar, extreme thirst, and the extreme urgency to urinate, among others. These can be driven by direct effect of progesterone or its downstream hormones or metabolites. Progesterone toxicity can lead to a clinical state of brittle adrenals, where adrenal gland function fluctuates between having too much cortisol followed by too low cortisol multiple times during a day.
  • Licorice is a popular sweetener found in soft drinks, food products, snacks, and herbal medicine. It is believed to be harmless. Extracting metabolite glycyrrhetic acid, it inhibits the enzyme 11-ß-hydroxysteroid dehydrogenase enzyme type 2, resulting in a the cortisol-induced mineralocorticoid effect. This tends to elevate sodium and reduce potassium. This aldosterone-like action accounts for its popular use on adrenal fatigue. Unfortunately, indiscriminate use can lead to pseudo-hyperaldosteronism. Adverse effects can also include myopathy, hypertension, neurological deficient, cardiac arrest, edema, ocular complications such as transient monocular or binocular visual loss/aberrations.
  • Dietary supplements containing Piper methysticum (kava) have been implicated in multiple cases of liver injury in humans. Its sedative and anxiety reducing benefits have been hampered with liver damage incidence when used with benzodiazepines and barbiturates. In fact over-the-counter sales of kava herbal preparations have been banned in some countries.
  • St John’s Wort, a popular herb, induces enzymes involved in the detoxification of drugs and other chemicals. Drug toxicity can be increased as a result, as when it is taken concurrently with paracetamol.

Arsenic poisoning and metabolite levels

  • Toxic metal incorporates, as part of our soil, food, and water chain and cannot be metabolized totally by the liver resulting in unwanted metabolite accumulation. aluminum, copper, arsenic, cadmium, lead, mercury, nickel, thallium are some of the most common culprits.
  • Major and trace nutritional elements that are part of the metabolite chain can also be problematic if not present in the right quantity in the body. They include calcium, potassium, chromium, copper, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium selenium, sodium, zinc.
  • Improper methylation of enzymatic reactions within the body can lead to excessive reactive metabolites. Genetically linked conditions such as MTHFR and pyroluria can be a trigger.
  • Many drugs interact with grapefruit. The list includes some cholesterol lowering drugs called statins, selected antibiotics, and certain cancer drugs. Older people are most at risk. Grapefruit contains furanocoumarins, which block an enzyme that normally breaks down certain medications in the body. Medication levels can grow toxic in the body if this is left unchecked.

Read Part 2 | Part 3

© Copyright 2017 Michael Lam, M.D. All Rights Reserved.