Sudan I (1-phenylazo-2-hydroxynaphthol) is a suspected human carcinogen causing tumors in the livers and urinary bladders of rats, mice, and rabbits. Here, we investigated for the first time the influence of Sudan I exposure on the expression of several biotransformation enzymes in the livers, kidneys, and lungs of rats concomitantly at the mRNA and protein levels and assayed their enzymatic activities. We also studied its effect on the formation of Sudan I-derived DNA adducts in vitro. Sudan I increased the total amounts of cytochrome P450 (P450) in all organs tested. Western blots using antibodies raised against various P450s, NADPH:P450 reductase, and NAD(P)H:quinone oxidoreductase 1 (NQO1) showed that the expression of P450 1A1 and NQO1 was induced in the liver, kidney, and lung of rats treated with Sudan I. The higher protein levels correlated with increased enzyme activities of P450 1A1/2 and NQO1. Furthermore, 9.9-, 5.9-, and 2.8-fold increases in the formation of Sudan I oxidative metabolites catalyzed by microsomes isolated from the liver, kidney, and lung, respectively, of rats treated with Sudan I were found. The relative amounts of P450 1A and NQO1 mRNA, measured by real-time polymerase chain reaction (RT-PCR) analysis, demonstrated that Sudan I induced the expression of P450 1A1 and NQO1 mRNA in the liver, kidney, and lung, and of P450 1A2 mRNA in kidney and lung. Finally, microsomes isolated from livers, kidneys, and lungs of Sudan I exposed rats more effectively catalyzed the formation of Sudan I-DNA adducts than microsomes from organs of control rats. This was attributable to the higher P450 1A1 expression. Because P450 1A1 is playing a major role in the bioactivation of Sudan I in rat and human systems, its induction by Sudan I may have a profound effect on cancer risk by this azo dye. In addition, the induction of P450 1A1/2 and NQO1 enzymes can influence individual human susceptibility to other environmental carcinogens and have an effect on cancer risk.
The objective of this study was to assess the efficacy and safety of liposomal heparin spray-a new formula of topical heparin delivery. This was a randomized, multicenter, controlled open clinical trial with 2 parallel groups. Forty-six outpatients with clinical signs of superficial venous thrombosis (SVT) were treated with either topical liposomal heparin spraygel (LHSG) (Lipohep Forte Spraygel, 4 puffs of 458 IU tid (n = 22) or with low-molecular-weight heparin (LMWH) (Clexane 40 mg once a day (n = 24), administered subcutaneously (sc). Main outcome measures were efficacy parameters (improvement of local symptoms-pain control and planimetric evaluation of erythema size, duplex Doppler assessment of thrombus regression) and safety parameters (documentation of adverse events, with particular reference to deep vein thrombosis [DVT] by duplex sonography, and patients' and investigators' assessment of drug tolerance). Patients' and investigators' subjective assessment of efficacy of treatment and change in basic biochemical parameters were defined as secondary outcome measures. Statistical analysis was performed with use of Wilcoxon test, Mann-Whitney U-test and Chi-square test. Regression of SVT-related symptoms, including pain, erythema, and thrombus presence, was shown as comparable in LHSG and LMWH groups. These results were corroborated by efficacy assessment by investigators and patients. Three cases of deep venous thrombosis in heparin spraygel and 1 in heparin sc group were reported. No significant adverse reactions were observed in the spraygel group, but 1 serious allergic reaction was observed in the LMWH group. Tolerance of new formula heparin was assessed as good. Heparin spraygel-a new topical mode of heparin application, seems a promising method of heparin delivery. This initial study has demonstrated comparable efficacy and safety of LHSG and LMWH in local treatment of SVT. These findings should be confirmed by further extensive study that will reach appropriate statistical power to support such conclusion, for despite heparin treatment, significant risk of DVT was demonstrated in both groups.
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