Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic sclerosis and lupus erythematosus

Abstract

The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3′ flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 pheno-types were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n=68) exhibited a significant increase (p<0.05) in the mutant Val-allele (OR=2.59) when compared to controls (n= 184). However, no significant differences in allele frequencies for Msp1 in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n=88) 75% and SSc (n=26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p<0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.