Assessment of subchronic toxicity and toxicokinetics of AG NPP709 in Sprague-Dawley rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Hedera helix L. (HH) leaves and Coptidis rhizoma (CR) have traditionally been used to treat respiratory conditions. AG NPP709, which is formulated using extracts of both these herbs, has been developed as an expectorant and antitussive. AIM OF THE STUDY: The objective was to evaluate the subchronic toxicity and toxicokinetic characteristics of AG NPP709 in laboratory rats. MATERIALS AND METHODS: AG NPP709 was orally administered to rats at doses of up to 2.0 g/kg/day for a duration of 13 weeks. Various health parameters were measured throughout the treatment period. At the end of the treatment, a necropsy was conducted and additional parameters were analyzed. Toxicokinetic analyses were also performed on hederacoside C and berberine, the active components of HH leaves and CR, respectively, in the plasma of rats treated with AG NPP709. RESULTS: AG NPP709-treated rats exhibited several health issues, such as reduced feed intake, altered differential white blood cell (WBC) count, increased plasma Alb/Glo ratio in females, and reduced kidney weight in males. However, these changes appeared to be incidental and fell within the typical range for healthy animals of this species. Additionally, toxicokinetic analysis of hederacoside C and berberine showed no accumulation in the plasma of rats during the repeated treatments with AG NPP709. CONCLUSIONS: Our study demonstrates that AG NPP709 does not have any harmful effects on rats under experimental conditions. Based upon these findings, the no observed adverse effect level of AG NPP709 can be estimated to be 2.0 g/kg/day in rats.

Association of the G134A and G184C Polymorphisms in the CYP1A1 Gene with Lung Cancer Incidence.

The G184C and G134A single nucleotide polymorphisms (SNPs) of the CYP1A1 gene result in Ala62Pro and Gly45Asp substitutions, respectively. Here, we tested whether these SNPs are associated with an alteration in lung cancer incidence. We examined 80 Korean subjects with lung cancer and 240 age- and sex-matched controls. For each subject, the CYP1A1 gene was PCR amplified and sequenced. We observed that the odds ratio (OR) for lung cancer was 3.37 higher in subjects with the G184C polymorphism than in controls (95% confidence interval (CI), 0.89~12.73, P = 0.07). In contrast, the OR for lung cancer was 1.23 in subjects with the G134A polymorphism compared to controls (95% CI, 0.68~2.20, P = 0.49). The G184C polymorphism exacerbated the effects of smoking on lung cancer development. Gene-smoking interaction analyses revealed that past or present smokers with the G184C polymorphism had a higher incidence of lung cancer (OR, 24.72; 95% CI, 4.48~136.31; P < 0.01) than control smokers (OR, 6.65; 95% CI, 2.72~16.28; P < 0.01). However, there was only a slight difference in the ORs for lung cancer between control smokers and smokers with the G134A polymorphism. These findings suggest that the G184C polymorphism, but not the G134A polymorphism, is associated with an increased risk of lung cancer.

Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis.

Oxidative stress has been suggested to be a major cause of male reproductive failure. Here, we investigated whether arsenic, which impairs male reproductive functions in rodent models, acts by inducing oxidative stress. Male 8-week-old ICR mice were given drinking water containing 20 or 40 mg/l sodium arsenite with or without 0.75 or 1.5 g/l of the antioxidant ascorbic acid for 5 weeks. The arsenic-treated mice showed decreased epididymidal sperm counts and testicular weights compared to untreated mice. These effects were reversed in mice that were co-treated with ascorbic acid. Similarly, arsenic treatment lowered the activities of testicular 3beta-hydroxysteroid dehydrogenase (HSD) and 17beta-HSD, which play important roles in steroidogenesis, and this was reversed by co-treatment with ascorbic acid. The testicles of arsenic-treated mice had decreased glutathione (GSH) levels (which correlate inversely with the degree of cellular oxidative stress) and elevated levels of protein carbonyl (a marker of oxidative damage to tissue proteins). Ascorbic acid co-treatment reversed both of these effects. Thus, ascorbic acid blocks both the adverse effects of arsenic on male reproductive functions and the arsenic-induced testicular oxidative changes. These observations support the notion that arsenic impairs male reproductive function by inducing oxidative stress.