Genetic polymorphism of drug-metabolizing enzymes and styrene-induced DNA damage.

A cross-sectional study was carried out on 48 workers exposed to styrene and 14 unexposed healthy controls in order to investigate the genotoxic potential of styrene exposure. DNA damage was assessed in peripheral blood leukocytes (WBCs) by the comet assay. Polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and the gene encoding microsomal epoxide hydrolase (EPHX) were characterized to assess their possible modifying role in styrene metabolism and subsequent DNA damage. Exposed workers showed significantly higher levels of DNA damage compared to controls. Among workers, the GSTM1 and GSTT1 polymorphisms significantly affected comet parameters. Subjects bearing a GSTM1pos genotype showed a significantly higher proportion of damaged nuclei compared to people lacking GSTM1-1 expression (GSTM1null), whereas GSTT1pos workers showed significantly lower DNA damage than GSTT1null individuals. Styrene-7,8-oxide (SO)-induced DNA damage was assessed in vitro in WBCs isolated from the healthy controls. A clear dose-response relationship at micromolar doses of SO was found for the whole group. WBCs collected from subjects bearing the homozygous wildtype GSTP1 genotype showed a significant protection compared to cells from subjects bearing at least one GSTP1 variant allele. The field survey confirms that styrene exposure is associated with increased DNA damage and indicates a modulating role for GSTM1 and GSTT1 genotypes. In vitro experiments suggest that the extent of SO-induced DNA strand breaks depends, at least in part, on interindividual differences in GSH-conjugation capabilities.

Prognostic significance of albuminuria in patients with renal cell cancer.

PURPOSE: A relationship between the urinary albumin excretion rate (UAE) and different types of tumors has been previously described but little is known about UAE and renal cell cancer (RCC). We evaluated the prognostic significance of UAE and its correlation with tumor clinicopathological findings in patients with RCC treated with recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha). Because rIL-2 and rIFN-alpha increase glomerular permeability, we also determined whether the first immunotherapy cycle induced a significant increase in UAE and whether it was related to tumor parameters. MATERIALS AND METHODS: A total of 51 consecutive patients with RCC were enrolled. Inclusion criteria were patient age at diagnosis younger than 70 years and serum creatinine less than 1.8 mg/dl. Patients with central nervous system metastases and diabetes mellitus were excluded. Nephrectomy was followed by systemic treatment with 1-month cycles of low dose rIL-2 and rIFN-alpha, which were repeated every 4 months, UAE was determined before and after the first treatment cycle. RESULTS: Univariate analysis showed that pre-cycle and post-cycle UAE greater than 30 mg/24 hours significantly influenced survival (p = 0.006 and 0.007, respectively). A multivariate model adjusted for age at onset, performance status, post-cycle UAE, tumor stage and grade, and metastases showed that pre-cycle UAE greater than 30 mg/24 hours had an independent prognostic role (p = 0.011). The first treatment cycle increased UAE 81.8% vs baseline (p = 0.002). The post-cycle vs pre-cycle increase was significant in patients with stages III-IV (p = 0.003) and grades 3-4 (p = 0.028) tumors. Pre-cycle and post-cycle UAE were significantly higher in stages III-IV than in stages I-II cases (p = 0.030 and 0.007, respectively). CONCLUSIONS: UAE is an independent prognostic factor that is related to disease stage in patients with RCC.

Assessment of biotransformation of the arene moiety of styrene in volunteers and occupationally exposed workers.

Styrene is a chemical widely used in the plastic industry. The main pathway of styrene metabolism in humans occurs via the oxidation to styrene-7,8-oxide (7,8-SO). The aim of this study was the investigation of a minor metabolic route, involving the oxidation of the arene moiety of styrene, by means of the characterization of the conjugated urinary metabolites of 4-vinylphenol (4-VP). 4-vinylphenol-glucuronide (4-VP-G) and -sulfate (4-VP-S), were measured by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) from 174 workers belonging to three cohorts recruited in European countries and from 26 volunteers exposed to 50 mg/m(3) (11.8 ppm) of styrene for 8 h. The 4-VP conjugates represented about 0.5-1% of the total excretion of styrene metabolites. Both 4-VP-G and 4-VP-S are eliminated with a monophasic kinetic, the glucuronide being excreted faster (half-time, 2.2 +/- 0.2 h) than the sulfate (half-time 9.7 +/- 1.7 h). The urinary 4-VP was found to be significantly correlated both with airborne styrene (r = 0.607, p < 0.001) and the sum of MA and PGA (r = 0.903, p < 0.001 in "end-of-shift" samples). Apart from 7,8-SO, 4-VP is the only styrene metabolite not shared with ethylbenzene and therefore thought to be a highly specific marker of styrene exposure. However, a measurable background excretion of 4-VP was also found in all urine samples from controls not occupationally exposed to styrene. This background appears to be highly correlated to smoking (p < 0.001) and possibly also to the dietary intake of styrene or 4-VP. Consequently, the use of 4-VP as a biomarker of styrene exposure is recommended for exposures exceeding 1 ppm.