Haufroid Vincent, Jakubowski Marek, Janasik Beata, Ligocka Danuta, Buchet Jean-Pierre, Bergamaschi Enrico, Manini Paola, Mutti Antonio, Ghittori Sergio, Arand Michael, Hangen Nina, Oesch Franz, Hirvonen Ari, Lison Dominique
Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Brussels, Belgium.
Pharmacogenetics. 2002 Dec;12(9):691-702. doi: 10.1097/00008571-200212000-00003.
In the field of occupational and/or environmental toxicology, the measurement of specific metabolites in urine may serve to assess exposure to the parent compounds (biological monitoring of exposure). Styrene is one of the chemicals for which biological monitoring programs have been validated and implemented in environmental and occupational medicine. However, inter-individual differences in the urinary excretion exist both for the main end-products (mandelic acid and phenylglyoxylic acid) and for its specific mercapturic acids (phenylhydroxyethylmercapturic acids, PHEMA). This limits to a certain extent the use of these metabolites for an accurate assessment of styrene exposure. In a group of 26 volunteers selected with relevant genotypes, and exposed to styrene vapours (50 mg/m3, 8 h) in an inhalation chamber, we evaluated whether genotyping or phenotyping relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1) may help to explain the observed inter-individual variability in the urinary metabolite excretion. Peripheral blood lymphocytes were used for genotyping and as reporter cells for the phenotyping of CYP2E1 and EPHX1. The GSTM1 genotype was clearly the most significant parameter explaining the variance in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so that systematic GSTM1 genotyping should be recommended routinely for a correct interpretation of PHEMA urinary levels. Variant alleles CYP2E1*6 (7632T>A) and His113EPHX1 were associated with a significant reduction of, respectively, the expression (P = 0.047) and activity (P = 0.022) of the enzyme in peripheral blood lymphocytes. In combination with GSTM1 genotyping, the phenotyping approach also contributed to improve the interpretation of urinary results, as illustrated by the combined effect of CYP2E1 expression and GSTM1 allelic status that explained 77% of the variance in PHEMA excretion and allows the recommendation of mercapturates as specific and reliable biomarkers of exposure to styrene.
在职业和/或环境毒理学领域，尿液中特定代谢物的测量可用于评估母体化合物的暴露情况（暴露的生物监测）。苯乙烯是一种在环境和职业医学中生物监测项目已得到验证并实施的化学物质。然而，主要终产物（扁桃酸和苯乙醛酸）及其特定的硫醚氨酸（苯羟乙硫醚氨酸，PHEMA）在尿排泄方面均存在个体差异。这在一定程度上限制了这些代谢物用于准确评估苯乙烯暴露的用途。在一组26名具有相关基因型的志愿者中，让他们在吸入室内暴露于苯乙烯蒸气（50 mg/m³，8小时），我们评估了对相关药物代谢酶（CYP2E1、EPHX1、GSTM1、GSTT1和GSTP1）进行基因分型或表型分析是否有助于解释观察到的尿代谢物排泄个体差异。外周血淋巴细胞用于基因分型，并作为CYP2E1和EPHX1表型分析的报告细胞。GSTM1基因型显然是解释尿中PHEMA排泄差异的最显著参数（GSTM1缺失受试者中低6倍；P < 0.0001），因此为正确解释尿中PHEMA水平，应常规推荐进行系统的GSTM1基因分型。CYP2E1*6（7632T>A）变异等位基因和His113EPHX1分别与外周血淋巴细胞中该酶的表达（P = 0.047）和活性（P = 0.022）显著降低相关。与GSTM1基因分型相结合，表型分析方法也有助于改进对尿液结果的解释，如CYP2E1表达和GSTM1等位基因状态的联合效应所表明的那样，该联合效应解释了PHEMA排泄差异的77%，并使得推荐硫醚氨酸作为苯乙烯暴露的特异性和可靠生物标志物成为可能。
