Glucuronidation is a when a functional group on an acceptor molecule (aglyclone) is conjugated with glucuronic acid. This creates hydrophilic and negatively charged glucuronides that cannot exit/enters cells without the aid of efflux transporters. The glucuronides are then often eliminated via bile or urine. Therefore, glucuronidation is considered to be a detoxification process or a defense mechanism that helps humans remove unwanted substances, therefore being important in the metabolism of drugs (commonly phase II preceded by hydrolysis, hydroxylation, or dealkylation, but is phase I in some cases) and their metabolites, as well as carcinogens, steroid hormones, bile acids, and bilirubin.
Once formed in the intestinal epithelial cells, glucuronides are excreted into the portal vein by the efflux transporters in enterocytes, from where they enter hepatocytes with the aid of hepatic uptake transporters to be excreted into bile.
This reaction uses UDP-glucuronic acid (UDPGA) as a co substrate, and is catalysed by a UDP-glucuronosyltransferase (UGT) enzyme. UGT’s are a diverse and drug specific enzyme family, with varying expression according to genetic encoding. Four UGT families have been identified in humans: UGT1, UGT2, UGT3 and UGT8.
Because the glucuronides are unable to passively permeate the cell membranes, the rate of glucuronidation is significantly influenced by the action of various efflux transporters pumping them out of the cell. The faster efflux rate can cause the rate of glucuronide formation to increase due to the removal of potentially inhibitory glucuronides.
Another distinction of glucuronidation is that the corresponding metabolites produced can be reconverted back into their original compound. In most mammalian tissue this process is very slow being dependant off glucuronidases, however is extremely repaid in the colon when they are in contact with intestinal microflora, which produces a large quantity and variety of glucuronidases that can readily convert glucuronides into aglycones. From there they can be reabsorped again to begin the process of recycling and recirculation, prolonging the exposure of the original compound.
In some cases the glucuronides can actually be more potent or more toxic than the parent drug.
*“Majority of the glucuronides are pharmacologically inactive, however, in certain incidences glucuronides have been shown to be equally or more effective than the parent drug. For example, morphine-6-glucuronide is reported to be 45–61 folds more potent” doi:10.1080/03602532.2017.1293682*
### Teaser on modulators of Glucuronidation
- Cigarette Smoking
- Cruciferous vegetables
- Liver size
- Oral Contraceptive Steroids
- Hormonal Status
- Ethnicity / Genetics
More to discuss on these soon…