Tissue distribution

Most of the drug-conjugating UGT isoforms are expressed in the liver, but are also present at variable levels in extrahepatic tissues, particularly tissues that are responsible for the absorption or excretion of drugs, such as intestine, lung, and kidney. Human hepatic UGTenzymes include UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B11, and UGT2B17.102 The gastrointestinal tract contains UGT1A1, UGT1A8 (restricted to the colon) and UGT1A10, whereas UGT1A7 seems to be localized to in the esophagus, stomach, and lung. Human kidney UGTenzymes include UGT1A8, UGT1A9, UGT1A10, and UGT2B7. In fact, UGT2B7 levels in the kidney are similar to those found in the liver.106 UGT2B transcripts are found in steroid-sensitive tissues, including the prostate (UGT2B17) and mammary tissues (UGT2B11 and UGT2B28).99 Glucuronidation reactions are also readily detectable in the brain and placenta.102

Intracellularly, UGTenzymes are embedded in the internal membrane and face the lumenal side of the endoplasmic reticulum which provides these enzymes ready access to the metabolic products of drug oxidation. However, this subcellular localization limits the access of substrates, cofactors, and glucuronidated products to and from the active sites of UGTenzymes. It is also responsible for the phenomenon known as 'latency' and contributes to difficulties in extrapolating in vivo effects of UGTenzymes from in vitro experiments using isolated tissue microsomes. To facilitate substrate access for in vitro studies of UGT activity, microsomes are often treated with low concentrations of detergent or a pore-former like allomethicin.

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