Abstract
CYP2E1 enzyme is related to nonalcoholic steatohepatitis (NASH) due to its ability for reactive oxygen species production, which can be influenced by polymorphisms in the gene. The aim of this study was to investigate hepatic levels, activity, and polymorphisms of the CYP2E1 gene to correlate it with clinical and histological features in 48 female obese NASH patients. Subjects were divided into three groups: (i) normal; (ii) steatosis; and (iii) steatohepatitis. CYP2E1 protein level was assayed in microsomes from liver biopsies, and in vivo chlorzoxazone hydroxylation was determined by HPLC. Genomic DNA was isolated for genotype analysis through PCR. The results showed that liver CYP2E1 content was significantly higher in the steatohepatitis (45%; p=0.024) and steatosis (22%; p=0.032) group compared with normal group. Chlorzoxazone hydroxylase activity showed significant enhancement in the steatohepatitis group (15%, p=0.027) compared with the normal group. c2 rare allele of RsallPstl polymorphisms but no C allele of Dral polymorphism was positively associated with CHZ hydroxylation, which in turn is correlated with liver CYP2E1 content (r=0.59; p=0.026). In conclusion, c2 allele is positively associated with liver injury in NASH. This allele may determine a higher transcriptional activity of the gene, with consequent enhancement in pro-oxidant activity of CYP2E1 thus affording liver toxicity.
Highlights
nonalcoholic steatohepatitis (NASH) is a progressive liver pathology associated to etiologic factors such as obesity, hyperlipidemia, insulin resistance, and type-II diabetes mellitus, with obesity being the most important (James and Day, 1998; Matteoni et al, 1999; Angulo et al, 1999; Ratziu et al, 2000)
Examples for genotypic analysis of Dra1, Rsa1, and Pst1 polymorphism are shown in Figure 1 (A and B), where patterns for obese women with different genotypes are observed after polymerase chain reaction (PCR) amplification and restriction enzyme digestion
The pathogenic mechanisms underlying the development of NASH are not completely understood, how apparently diverse etiologies such as alcohol consumption and obesity can give rise to similar histological features (Lieber, 2004; Ishii, 2004)
Summary
NASH is a progressive liver pathology associated to etiologic factors such as obesity, hyperlipidemia, insulin resistance, and type-II diabetes mellitus, with obesity being the most important (James and Day, 1998; Matteoni et al, 1999; Angulo et al, 1999; Ratziu et al, 2000). This disorder is observed in patients with no history of significant alcohol consumption, histologically it resembles alcohol-induced liver injury (Ludwig et al, 1980).
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