OBJECTIVE -A high prevalence of diabetes has been reported in patients with hepatitis C virus (HCV) infection. Both diabetes and HCV infection are associated with high serum ferritin levels. Although HCV infection could be the main factor responsible for the high ferritin levels, it is also possible that diabetes rather than HCV infection might be a major contributor to the high ferritin levels observed in patients with HCV infection. The aim of this study was to investigate the contribution of diabetes to the high ferritin levels observed in HCV-infected patients with chronic hepatitis. RESEARCH DESIGN AND METHODS-A total of 634 noncirrhotic individuals were prospectively recruited at a university hospital. According to the HCV antibody status and the presence of diabetes, the subjects were divided into four groups: group A (anti-HCV-positive diabetic patients, n ϭ 53), group B (anti-HCV-negative diabetic patients, n ϭ 242), group C (anti-HCV-positive nondiabetic patients, n ϭ 191), and group D (anti-HCV-negative nondiabetic control subjects, n ϭ 148). Multiple regression analyses were used to explore the variables independently related to ferritin levels.RESULTS -Serum ferritin levels in group A were significantly higher than in the other groups (A Ͼ B, P Ͻ 0.01; A Ͼ C, P Ͻ 0.001; A Ͼ D, P Ͻ 0.001). Ferritin levels were higher in group B than in group D (P ϭ 0.001). However, group C has ferritin values similar to those of group D. In multivariate analyses, diabetes but not HCV infection was independently related to serum ferritin concentrations.CONCLUSIONS -Diabetes rather than HCV infection itself is the main factor associated with the increased ferritin levels detected in patients with HCV infection. Therefore, the presence of diabetes should be taken into account when iron metabolism is evaluated in HCV-infected patients. Diabetes Care 27:2669 -2675, 2004I ncreasing evidence exists suggesting an association between hepatitis C virus (HCV) infection and diabetes. In this regard, a high prevalence of HCV infection has been found among diabetic patients (1-3). Alternatively, a high prevalence of both diabetes and impaired fasting glucose has also been reported in HCV-infected patients in comparison with other liver diseases (4 -8). The NHANES III (Third National Health and Nutrition Examination Survey) has shown that people Ͼ40 years of age with HCV infection were more than three times more likely to have type 2 diabetes than those without HCV infection (9). In addition, Mehta et al. (10) have reported that preexisting HCV infection may increase the risk of type 2 diabetes in individuals with recognized diabetes risk factors. Furthermore, Shintani et al. (11) have recently shown direct experimental evidence for the contribution of HCV in the development of insulin resistance using HCV core transgenic mice.Type 2 diabetes is a condition frequently associated with elevated levels of serum ferritin (12,13). An association of high serum ferritin concentration and glucose intolerance and insulin resistance in healt...

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retransplantation. In contrast, patient MLP received a standard course of immunosuppressants. HCV RNA was extracted from plasma by the acid guanidinium thiocyanate-phenol-chloroform method (3). Isolated HCV RNA was reverse transcribed into cDNA and PCR amplified in a single-tube reaction (reverse transcription PCR; Perkin-Elmer) for 35 cycles (5 cycles of 94°C for 2 min, 50°C for 2 min, and 72°C for 3 min, and 30 cycles of 94°C for 1.5 min, 60°C for 2 min, and 72°C for 3 min) with specific oligonucleotides designed, on the basis of published HCV sequences (4, 20), to amplify the 5' UTR (5' AAGGATCCGGTGCACGG TCTACGAGACCT 3' and 5' TTGCATGCCAGCCCCCTG ATGGGGGCGACACTCC 3') and E2/NS2 (5' GACTACTG CAGTTGCGCTFCCACTCTGGT 3' and 5' GGAGAATTC

The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.