Thiopurine Methyltransferase

Thiopurine methyltransferase (TPMT) is a methylating enzyme whose gene is encoded on chromosome 6. It plays an important role in the catabolism of 6-MP and its prodrug azathioprine, thus preventing generation of thioguanine nucleotides. Early studies revealed that TPMT activity is inherited as an autosomal codominant trait.106 About 1 in 300 individuals carry two mutant TPMT alleles, thus resulting in deficient activity. Approximately 10% of the population are heterozygotes with intermediate TPMT activity.107 It has been shown that the various single-nucleotide polymor phisms do not result in altered levels of mRNA or TPMT protein. However, these mutations render the translated protein susceptible to degradation through the ubiquitin-pro-teasome system, decreasing the half-life to 30 minutes compared to 18 hours for the wild-type protein.108 TPMT*3A, TPMT*3C, and TPMT*2 mutant alleles, which harbor point mutations resulting in amino acid substitutions, account for more than 95% of deficient TPMT activity among whites.

As there is no endogenous substrate for TPMT, individuals with defective enzyme activity are asymptomatic until exposure to thiopurine drugs results in severe myelosuppres-sion that may be life threatening. On the other hand, individuals with high or high-normal TPMT are relatively resistant to the action of thiopurine drugs and thus may not achieve clinical remission if these drugs are used at standard dosages. An allele with increased TPMT activity has been described. TPMT activity can be influenced by various factors such as age and renal function. TPMT activity in red blood cells serves as a surrogate marker for TPMT activity in other tissues.

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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