Dapsone acetylation by human liver arylamine N-acetyltransferases and interaction with antiopportunistic infection drugs.

Dapsone is used in the treatment of Pneumocystis carinii pneumonia, an opportunistic infection that afflicts acquired immunodeficiency syndrome (AIDS) patients. Inhibition of N-acetyltransferase (NAT)-dependent acetylation of dapsone could increase peak plasma concentrations of dapsone and shift the biotransformation pathway to the P450-mediated formation of a toxic metabolite of dapsone, the hydroxylamine. Therefore, we have determined using human liver cytosol and bacterially expressed NATs, the NAT isoform responsible for acetylating dapsone and the potential for antiopportunistic infection drugs to inhibit this metabolic pathway.

The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors.

Bladder cancer provides the most definitive example for an association between environmental agents and cancer. However, in the absence of industrial occupational exposure, the primary carcinogen is rarely identified, and the mechanisms involved in cancer formation are poorly understood. The environmental procarcinogen hypothesis of tumour pathogenesis proposes that many carcinogens require metabolic activation by drug metabolizing enzymes to form the proximate carcinogen.

Correlation of polymorphic expression of CYP2D6 mRNA in bladder mucosa and tumor tissue to in vivo debrisoquine hydroxylase activity.

Debrisoquine hydroxylase activity has been attributed to CYP2D6 and poor metabolizers of debrisoquine have a reduced relative risk of developing aggressive bladder cancer. Production of a proximate carcinogen could occur in liver or bladder mucosa. However, it is not known if CYP2D6 is expressed in human bladder mucosa.

Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans.

The present study assesses the role of members of the human CYP2C subfamily in the 4'-hydroxylation of (S)-mephenytoin. When recombinant CYP2C proteins were expressed using a yeast cDNA expression system, 2C19 stereospecifically 4'-hydroxylated (S)-mephenytoin with a turnover number at least 10 times higher than that of human liver microsomes. 2C9 (both Ile359 and Leu359 alleles) and 2C18 (Thr385 and Met385 alleles) metabolized this substrate at a rate 100-fold lower than 2C19, and metabolism by these 2C proteins was not stereospecific for the S-enantiomer.