Uridine Diphosphate Glucuronosyltransferase

Uridine diphosphate glucuronosyltransferase (UGT) is an enzyme that catalyzes the phase II catabolic reaction in which uridine diphosphate glucuronic acid is conjugated with drugs or poorly soluble endogenous substrates. There are two gene families (UGT1 and UGT2), each of which has various iso-forms. The most important of these isoforms is UGT1A1, which is encoded on chromosome 2q37. Polymorphisms of the gene encoding UGT1A1 give rise to the hyperbilirubinemia phenotype of the rare Crigler-Najjar syndrome and the relatively common Gilbert syndrome.

UGT1A1 plays an important role in the metabolism of the active metabolite of irinotecan, SN38 by changing it into the more polar SN 38 glucuronide, which is mainly excreted in the bile. Reduced UGT1A1 expression, often associated with elevated levels of unconjugated bilirubin, is inherited in an autosomal-recessive pattern. Polymorphisms in the number of TA repeats in the promoter region, which is inversely related to UGT1A1 enzyme activity, constitute the most common abnormality. The wild-type promoter region has a (TA)6TAA sequence whereas the most common mutation results in an extra TA, thus the sequence becoming (TA)7TAA (UGT1A1*28). Patients with Gilbert syndrome are homozy-gous for this promoter variation, which leads to a 70% reduction in UGT1A1 expression. (TA)7TAA homozygosity occurs in about 0.5% to 23% in various populations. Other mutations in the promoter region of UGT1A1 gene alter transcription and have been associated with deficient or increased UGT1A1 activity.

Patients with the UGT1A1*28 allele are susceptible to severe, at times life-threatening, toxicities of irinotecan, mainly leukopenia and diarrhea.

A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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