Definition
Glucuronidation refers to an intracellular metabolic reaction in which an endogenous or exogenous substrate is conjugated to glucuronic acid. The organism thereby makes the substrates more water soluble so that they can be rapidly excreted in the urine. Glucuronidation belongs to phase II metabolism (conjugations).
- UDP: uridine diphosphate
- UGT: UDP-glucuronosyltransferase
Enzymes involved
Glucuronidation is an enzymatic reaction catalyzed by UDP-glucuronosyltransferases (abbreviation: UGT). Various isozymes exist, which are classified into families and subfamilies:
- UGT1: family 1
- UGT1A: subfamily A
- UGT1A1: Individual enzyme or gene (italics: )
UGT are located intracellularly at the endoplasmic reticulum. The most important organ for metabolism is the liver. But UGT is also found extrahepatic at various other organs. Alcohols, phenols, carboxylic acids, amines and thiols are accepted as substrates. One speaks of -, -, – and -glucuronides. On the one hand, the active ingredients can be conjugated directly. On the other hand, it is also possible to introduce a corresponding functional group in phase I metabolism, especially CYP450 isozymes.
Endogenous substrates
As mentioned above, UGTs are not only essential for xenobiotics but also for endogenous substrates. These include bilirubin, bile acids, thyroid hormones, fat-soluble vitamins, and steroid hormones. If the enzymes are not sufficiently active, diseases can develop. For example, Meulengracht’s disease is a result of insufficient activity of UGT1A1, which conjugates bilirubin.
Significance in drug metabolism
Many pharmaceutical agents and their metabolites are substrates of UGT and are glucuronidated. The following list shows only a small selection:
- Paracetamol
- Opioids
- NSAIDS
- Estrogens: estradiol, ethinyl estradiol
- Tricyclic antidepressants
- Naloxone
- Benzodiazepines
- Lamotrigine
- Ezetimibe
Glucuronidation changes the water solubility of a drug and usually its pharmacologic activity. The metabolites may be active or inactive or interact with a new drug target. A well-known and typical example of an active metabolite is morphine-6-glucuronide (M6G), which is much more potent than morphine. Retinoic acids are also activated by conjugation.
Drug Interactions
Like cytochromes P450, UDP-glucuronosyltransferases can be inhibited and induced, causing interactions along the way. Examples of inhibitors are immunosuppressants and of inducers are the rifamycins, barbiturates, and some antiepileptic drugs.
