Glucuronic acid

Glucuronidation

It is possible to exhaust the body's supply of glucuronic acid by combining multiple drugs/substances whose metabolism and excretion are dependent on glucuronidation. Although most such substances have secondary metabolic routes which become prominent following GCA depletion, the rate of metabolism is reduced enough to produce a marked accumulation of all GCA substrates in the system; this often increases drug concentrations in the blood by medically relevant amounts. In the most severe cases, permanent and debilitating organ damage (particularly of the liver, kidneys, heart, and brain), and even death, have been known to occur. Ethanol, morphine, paracetamol (acetaminophen), cyclooxygenase inhibitors (NSAIDs), endogenous steroids, and certain benzodiazepines are all capable of contributing to GCA depletion, with ethanol and acetaminophen being the most commonly implicated substances involved in cases of accidental overdoses which have been positively attributed to glucuronic acid depletion.

Excessive quantities of GCA can also be hazardous to health. Tobacco smoke, most barbiturates, and some carbamates are known to stimulate GCA production. Increased GCA activity results in a decrease of the concentration and metabolic half-life of glucuronic acid substrates, causing the plasma levels of glucuronidated drugs to fall below their therapeutic threshold. Excessive glucuronidation of the substrates may result in an inadequate response to traditional doses of affected medications and, unless the drug has a very wide therapeutic index, will generally result in the acute failure of the pharmacotherapy and necessitate the transition from one or more implicated drugs to an equivalent regimen of non-glucuronidated alternatives. A select number of antidepressants and a wide range of anti-psychotic agents are glucuronidation ligands, but due to their delayed mechanism of action and pharmacokinetic properties the decrease of their plasma concentrations may not be immediately apparent and tends to present as a sudden and intense relapse of symptoms instead of a gradual regression to the behaviors and thought patterns exhibited by the patient prior to the initiation of their pharmacological treatment.

Role in disease

Glucuronic acid, as well as the glucuronidated metabolite of ethanol, ethyl glucuronide (ETG), acts on toll-like receptor 4 to aggravate both acute and chronic inflammatory conditions and increases the perceived severity of pain in patients with chronic pain conditions, via up-regulation of the production and release of endogenous inflammatory signaling molecules within the body. Long-term agonism of the TLR4 receptor (such as that which occurs from GCA, ETG, and opiates) results in chronically painful conditions being perceived as considerably more severe than they did previously, while pre-existing, tolerable yet occasionally painful activities can become more painful than before and will begin to be aggravated by briefer and less physically demanding activities. It also can cause equally painful responses to decreasingly noxious (irritating) stimuli, eventually resulting in considerable agony from stimuli which would not cause any amount of pain to most individuals.^[3]