Human UDP‐glucuronosyl transferases: Chemical defence, jaundice and gene therapy

Abstract

Human UDP-glucuronosyltransferases (UDPGTs) are a family of enzymes which detoxify many hundreds of compounds by their conjugation to glucuronic acid, rendering them both harmless and more water soluble, hence, excretable. The level of expression of each UDPGT isoform in the body is the result of interplay between temporal, tissue-specific and environmental regulators. This complexity contributes to the difficulty in predicting the metabolic fate of compounds. Genetic defects and polymorphisms affecting individual isoform activities have deleterious and potentially lethal effects, as exemplified by the severe hyperbilirubinaemia observed in Crigler-Najjar Syndrome. Such severe genetic defects in bilirubin glucuronidation are obvious candidates for antenatal screening and gene therapy.

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

“…In support of this, the common domain and the isoform-specific 5' half of the four UGT1 cDNAs colocalized to chromosome 2 at 2q.37 (10). Owens et al (11) described the existence of a gene complex by the isolation of overlapping cosmid clones containing six alternative substratedetermining first exons upstream of the four exons that make up the common domain.…”

Anticarcinogenic Factors in Plant Foods: A New Class of Nutrients?

“…In a study in which rats were fed a diet supplemented with fish oil there was a 3-fold increase in UDPGT after 4 weeks compared to a control group given a fat-free diet (Dannenberg & Yang, 1992). Cytochrome P450 1A2 and 2E1 are also induced by fish oils (Yo0 et al 1990), and regulation of expression of UDPGT, like P450 1A1/2, is influenced by the Ah receptor (Brierley & Burchell, 1993). Expression is also influenced by the peroxisome proliferator receptor (Brierley & Burchell, 1993).…”

“…Cytochrome P450 1A2 and 2E1 are also induced by fish oils (Yo0 et al 1990), and regulation of expression of UDPGT, like P450 1A1/2, is influenced by the Ah receptor (Brierley & Burchell, 1993). Expression is also influenced by the peroxisome proliferator receptor (Brierley & Burchell, 1993). The effect of non-nutrients on UDPGT expression has been poorly studied in humans.…”

Three Japanese patients with Crigler-Najjar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase

“…On the basis of the structure of the gene for human bilirubin UGT, the genetic backgrounds of patients with CN-I have been elucidated. While almost all reported patients with the disease have homozygous nonsense or deletion mutations in the coding region of the gene (Brierley and Burchell, 1993), a few cases with homozygous missense mutations were found recently (Bosma et al, 1992b;Erps et al, 1994). By screening, we found four patients who suffered from CN-I in Japan.…”