Glucuronidation

Glucuronidation, more correctly glucuronosylation, is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosidic bonds.

Mechanism

Glucuronidation consists of transfer of the glucuronic acid component of UDP-glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase.

UDP-glucuronic acid (glucuronic acid linked via a glycosidic bond to uridine diphosphate) is an intermediate in the process and is formed in the liver. One example is the N-glucuronidation of an aromatic amine, 4-aminobiphenyl, by UGT1A4 or UGT1A9 from human, rat, or mouse liver.

The substances resulting from glucuronidation are known as glucuronides (or glucuronosides) and are typically much more water-soluble than non-glucuronic acid-containing substance from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver). Hormones may also be glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of substances. Sometimes toxic substances are also less toxic after glucuronidation.

The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism.

Sites

Glucuronidation occurs mainly in the liver, although the enzyme responsible for its catalysis, UDP-glucuronyltransferase, has been found in all major body organs (e.g., intestine, kidneys, brain, adrenal gland, spleen, and thymus).

General influencing factors

Various factors affect the rate of glucuronidation, in turn causing increased or decreased glucuronidation of various substances, in turn affecting their clearance. Generally, an increased rate of glucuronidation results in less effect of affected drugs or compounds, and vice versa.

Factor		Effect on glucuronidation	Main drugs or compounds affected
Age	Infant	↑	Chloramphenicol, morphine, paracetamol, bilirubin, steroids
	Elderly	↑ or unchanged	No change found for paracetamol, oxazepam, temazepam, or propranolol. Decreased clearance found for codeine-6-glucuronide, and decreased unbound clearance for oxazepam in the very elderly.
Gender	Females	↓	Clearance higher in males for paracetamol, oxazepam, temazepam, and propranolol. Possible additive role with CYP1A2 resulting in higher clozapine and olanzapine concentrations in females
	Males	↑
Body habitus	Overweight	↑	Clearance of lorazepam, oxazepam, temazepam, and paracetamol likely the result of an increase in liver size and quantity of enzyme
	Underweight/malnourished	↓	Chloramphenicol, paracetamol
Disease states	Fulminant hepatitis, cirrhosis	↓	Zidovudine, oxazepam, lamotrigine
	Hypothyroidism	↓	Oxazepam, paracetamol
	HIV	↓	Paracetamol
Tobacco smoking		↑	Propranolol, oxazepam, lorazepam, paracetamol. Possible additive role with CYP1A2 induction causing decreased clozapine and olanzapine concentration.

Affected drugs

Many drugs which are substrates for glucuronidation as part of their metabolism are significantly affected by inhibitors or inducers of their specific glucuronisyltransferase types:

Substrate	Inhibitors of glucuronidation	Inducers of glucuronidation,
Morphine	Amitriptyline Clomipramine Clonazepam Diazepam Flurnitrazepam Lorazepam Nitrazepam Oxazepam Codeine	Rifampin Tobacco smoking Phenobarbital
Oxazepam	Ethinylestradiol Fenoprofen Ibuprofen Ketoprofen Naproxen	Phenobarbitone Phenytoin
Bilirubin		Phenobarbital
Paracetamol	Ethinylestradiol Probenecid Propranolol
Androsterone	Promethazine Chlorpromazine
Carbamazepine- 10,1 1-transdiol	Valproic acid
Codeine	Amitriptyline Diclofenac
Lamotrigine	Sertraline Valproic acid
Lorazepam	Ethinylestradiol Probenecid Valproic acid
Temazepam	Probenecid
Testosterone	Amitriptyline Chlorpromazine Imipramine Promethazine
Zidovudine	Probenecid Valproic acid