Morphine-6-glucuronide
Encyclopedia
Morphine-6-glucuronide (M6G) is a major active metabolite
of morphine
, and as such is the molecule
responsible for much of the pain-relieving effects of morphine (and thus heroin). M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7
(UGT2B7). M6G can accumulate to toxic levels in kidney failure.
The μ-opioid receptor
subtype 3 appears to be activated (agonized) by morphine-6β-glucuronide but not morphine itself. This finding is also true of certain heroin metabolites (6-MAM) but not morphine proper.
activity of M6G (in animals) was first noted by Yoshimura.
Subsequent work at St Bartholomew's Hospital
, London in the 1980s, using a sensitive and specific HPLC assay
, accurately defined for the first time the metabolism of morphine, and the abundance of this metabolite (along with morphine-3-glucuronide
and morphine-3,6-diglucuronide, both considered inactive metabolites).
It was postulated that renal impairment would result in accumulation of the renally-excreted active agent M6G, leading to potentially fatal toxicity such as respiratory depression. The frequent use of morphine in critically ill patients, and the common occurrence of renal failure
in this group implied that M6G accumulation could be a common, but previously unanticipated problem. The first studies demonstrated massive levels of M6G in 3 patients with renal failure, which resolved as kidney
function returned. Accumulation of M3G and M6G also decrease with return of renal function after renal transplantation.
A key step in defining the importance of M6G in man came in 1992 when the substance was artificially synthesised and administered to patients with pain, the majority of whom described pain relief.
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, and as such is the molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
responsible for much of the pain-relieving effects of morphine (and thus heroin). M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7
UGT2B7
UGT2B7 is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain...
(UGT2B7). M6G can accumulate to toxic levels in kidney failure.
The μ-opioid receptor
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
subtype 3 appears to be activated (agonized) by morphine-6β-glucuronide but not morphine itself. This finding is also true of certain heroin metabolites (6-MAM) but not morphine proper.
History of discovery
This analgesicAnalgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
activity of M6G (in animals) was first noted by Yoshimura.
Subsequent work at St Bartholomew's Hospital
St Bartholomew's Hospital
St Bartholomew's Hospital, also known as Barts, is a hospital in Smithfield in the City of London, England.-Early history:It was founded in 1123 by Raherus or Rahere , a favourite courtier of King Henry I...
, London in the 1980s, using a sensitive and specific HPLC assay
High performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
, accurately defined for the first time the metabolism of morphine, and the abundance of this metabolite (along with morphine-3-glucuronide
Morphine-3-glucuronide
Morphine-3-glucuronide is a metabolite of morphine produced by UGT2B7. It is not active as an opioid agonist, but does have some action as a convulsant, which does not appear to be mediated through opioid receptors; it is mediated by GABA/glycinergic system...
and morphine-3,6-diglucuronide, both considered inactive metabolites).
It was postulated that renal impairment would result in accumulation of the renally-excreted active agent M6G, leading to potentially fatal toxicity such as respiratory depression. The frequent use of morphine in critically ill patients, and the common occurrence of renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
in this group implied that M6G accumulation could be a common, but previously unanticipated problem. The first studies demonstrated massive levels of M6G in 3 patients with renal failure, which resolved as kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
function returned. Accumulation of M3G and M6G also decrease with return of renal function after renal transplantation.
A key step in defining the importance of M6G in man came in 1992 when the substance was artificially synthesised and administered to patients with pain, the majority of whom described pain relief.