Silvestri Laura, Sonzogni Laura, De Silvestri Annalisa, Gritti Chiara, Foti Luciana, Zavaglia Claudio, Leveri Michela, Cividini Agostino, Mondelli Mario U, Civardi Emilio, Silini Enrico M
Associazione Studi Avanzati Epatiti Virali, Bonate Sotto (BG), Italy.
Int J Cancer. 2003 Apr 10;104(3):310-7. doi: 10.1002/ijc.10937.
Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the chi(2) test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects.
癌症风险可能受到内源性或环境毒素暴露的影响。参与致癌物代谢激活/解毒的多态性酶可能是导致个体风险差异的原因。我们研究了细胞色素P450超家族的五种酶，即CYP1A1、CYP1A2、CYP2D6、CYP2E1和CY3A4的多态性，将其作为丙型肝炎病毒感染患者肝病进展和癌症的风险因素。通过聚合酶链反应（PCR）限制性片段长度多态性或等位基因特异性PCR进行CYP基因分型。研究考虑了疾病的不同阶段，具体如下：90例无症状携带者、87例慢性肝炎患者、92例肝硬化患者和91例肝细胞癌（HCC）患者。从99名献血者中获取参考等位基因频率。使用卡方检验比较各分类之间的等位基因分布。计算优势比（OR）和95%置信区间（CI）以表达相对风险。通过对应分析和逻辑回归建立独立关联模型。与携带者相比，肝病患者中CYP1A1高诱导性等位基因MspI m2和Val的频率增加；未发现与HCC有特定关联。与包括肝硬化在内的其他丙型肝炎病毒感染类别相比，HCC患者中高活性CYP2E1 c2等位基因的比例较低。CYP2D6慢代谢者（PM）基因型在健康受试者（7.1%）和携带者（11.1%）中比在肝炎/肝硬化患者（4.6%）和HCC患者（1.2%）中更为常见。多变量分析证实了这一点。PM基因型可预防疾病进展，因为OR与疾病阶段成比例降低。非PM个体的HCC诊断年龄提前。CYP1A2和CYP3A4基因未发现差异。CYP基因的多态性变体可能导致丙型肝炎病毒感染受试者的肝病进展和HCC风险。
