Scleroderma is associated with differences in individual routes of drug metabolism: A study with dapsone, debrisoquin, and mephenytoin

Abstract

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Genetic polymorphism of CYP2C19 in Maharashtrian population

“…As a result pronounce genetically determined differences in the disposition of these drugs may affect their efficacy and toxicity. CYP2C19 polymorphism also may contribute to a metabolic predisposition to certain diseases including nonaggressive bladder cancer [22], lung cancer (squamous cell carcinoma) [23], scleroderma or systemic sclerosis [24], and the eosinophilia-myalgia syndrome [25]. Thus defining the frequency of this polymorphism in different populations has considerable epidemiologic importance.…”

The CYP2C19 Enzyme Polymorphism

“…Focusing only on a defect in oxidative metabolism ignores the role that defects in conjugation may play in the detoxification process and their concomitant impact on the disease or its complications. The initial effort to assess polymorphisms in CYP2C19 and acetylation in scleroderma [45] showed some promise in combining these two elements. Today, more conjugative polymorphisms are known that could be evaluated simultaneously with the CYP2C19 genotype for their potential contribution to disease processes and complications.…”

“…From this initial observation, numerous studies have followed defining the autosomal recessive inheritance of this deficiency [3,4], its frequency in various populations throughout the world [5][6][7][8][9][10][11][12][13], the gene responsible for this metabolism [14,15], and the molecular basis for this deficiency [16][17][18][19][20][21][22]. Researchers throughout the world have investigated associations between the defect in S-mephenytoin 4)-hydroxylation and metabolism of other drugs , as well as possible associations between this deficiency and disease [44][45][46][47][48][49][50]. Today, 3-D models of the active enzyme site are being developed to predict which chemicals are likely substrates and what metabolites might be formed [51][52][53].…”

N-acetyltransferase polymorphism in patients with Behçet's disease

“…Although there are con¯icting results with respect to the association of NAT2-acetylation status and risk of developing SLE [9,19], there is some evidence that NAT2-acetylation polymorphism has been linked to susceptibility to certain autoimmune diseases [8,9,10]. An overrepresentation of NAT2 slow acetylators was found among patients with SLE [8,9].…”

“…Certain NAT2 traits may contribute to the occurrence of adverse drug eects [4] and, moreover, are susceptibility factors for certain malignancies such as bladder or lung cancer [5,6,7]. In addition, NAT2-acetylation polymorphism has been linked to susceptibility to certain autoimmune diseases such as systemic lupus erythematosus (SLE) [8,9] and scleroderma [10].…”