Herb Sanqi-Derived Compound K Alleviates Oxidative Stress in Cultured Human Melanocytes and Improves Oxidative-Stress-Related Leukoderma in Guinea Pigs.

Sanqi, a traditional Chinese herb, is widely used for cardiovascular diseases, and its neuroprotective effects against oxidative stress were recently discovered. The purpose of this study was to investigate whether Sanqi-derived compound K (Sanqi-CK), an active metabolite of Sanqi, could protect melanocytes from oxidative stress. Cultured human primary skin epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of Sanqi-CK. Sanqi-CK exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, treatment with Sanqi-CK reversed the decreased glutathione reductase activity and decreased ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) seen in H2O2-treated melanocytes. Furthermore, topical application of Sanqi-CK alleviated leukoderma in guinea pigs, a disorder characterized by melanocyte cell death resulting from rhododendrol-induced oxidative stress. Taken together, these data suggest that Sanqi-CK protects melanocytes against oxidative stress, and its protective effects are associated with modulating the redox balance between GSH and GSSG and activating glutathione reductase. Thus, Sanqi-CK may be a good candidate for preventing melanocyte loss in oxidative-stress-associated pigmentary disorders.

RIFM fragrance ingredient safety assessment, isobutyl alcohol, CAS Registry Number 78-83-1.

The existing information supports the use of this material as described in this safety assessment. Isobutyl alcohol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that isobutyl alcohol is not genotoxic. Data on isobutyl alcohol provide a calculated MOE >100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across material isoamyl alcohol (CAS # 123-51-3) show that there are no safety concerns for isobutyl alcohol for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; isobutyl alcohol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material and the exposure to isobutyl alcohol is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; isobutyl alcohol was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

Invasion inhibitors of human fibrosarcoma HT 1080 cells from the rhizomes of Zingiber cassumunar: structures of phenylbutanoids, cassumunols.

The methanolic extract and its EtOAc-soluble fraction from the rhizomes of Zingiber cassumunar inhibited invasion of human fibrosarcoma HT 1080 cells. From the EtOAc-soluble fraction, eight new phenylbutanoids, cassumunols A-H, were isolated together with 30 known constituents. The structures of new phenylbutanoids were elucidated on the basis of chemical and physicochemical evidence. Principal constituents were examined the inhibitory effects on the invasion of HT 1080 cells. Among them, phlain I and III, (E)-1-(3,4-dimethoxyphenyl)buta-1,3-diene, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene, and (-)-ß-sesquiphellandrene showed anti-invasion effects. Interestingly, (E)-1-(2,4,5-trimethoxyphenyl)buta-1,3-diene [inhibition (%) 46.8 ± 7.2 (p<0.05) at 30 µM] significantly inhibited the invasion, and only a weak cytotoxic effect was observed.

Solvent-induced ototoxicity in rats: an atypical selective mid-frequency hearing deficit.

Most previous reports of ototoxicity following exposure to several volatile organic solvents have restricted testing to the low- and mid-frequencies (2-20 kHz) of the hearing range in the rat (0.25-80 kHz). We report here that inhalation exposure to styrene, mixed xylene, toluene, and 1,1,2-trichloroethylene resulted in hearing dysfunction only in the mid-frequency range and spared function at lower and higher frequencies. Adult male Long Evans rats were exposed via inhalation (whole body) in flow-through chambers. The following exposures were used: styrene, 1600 ppm; 1,1,2-trichloroethylene, 3500 ppm; toluene, 2500 ppm; mixed xylenes, 1800 ppm (N = 7-8 per group, 8 h/day for 5 days), and n-butanol, 4000 ppm (N = 10/group, 6 h/day for 5 days). Testing of auditory function was conducted 5 to 8 weeks after exposure using reflex modification audiometry (RMA). RMA thresholds were determined for frequencies from 0.5 to 40 kHz. Results indicated increased RMA thresholds for the mid-frequency tones (e.g., 8 and 16 kHz), but not higher or lower tones, for all solvents except n-butanol. Toluene and xylene also increased thresholds at 24 kHz. These data indicate that for those solvents reported thus far to cause hearing loss, the deficit is restricted to mid-frequencies in rats.

Comparative toxicities of the naturally occurring nitrile 1-cyano-3,4-epithiobutane and the synthetic nitrile n-valeronitrile in rats: differences in target organs, metabolism and toxic mechanisms.

Toxic but sublethal oral doses of 125 mg/kg (1.1 mmol/kg) of the cruciferous nitrile, 1-cyano-3,4-epithiobutane (CEB), or 175 mg/kg (2.1 mmol/kg) of its synthetic saturated analogue, n-valeronitrile (VN), were given by gavage to male CDF (F-344/CrlBr) rats once daily for 1, 2 or 3 days, in order to compare target tissues and to observe structure-activity relationships between the nitriles. CEB-induced changes included degeneration and necrosis of the pars recta of the renal proximal tubules, ulceration and necrosis in the forestomach, a mild increase (4.5-fold) in daily urinary thiocyanate (SCN-) excretion (only in rats treated for 3 days) and 1.5- to 2.4-fold increases in hepatic and pancreatic non-protein thiol (RSH) concentrations (in all CEB-treated groups). In VN-treated rats, there were no consistent histological changes but 95- to 170-fold increases in daily urinary SCN- excretion, delayed clinical signs of cyanide toxicity and minimal effects on tissue RSH concentrations. These results indicate different toxic mechanisms for VN and CEB. The nephrotoxic effects of CEB were very similar to those of 1-cyano-2-hydroxy-3,4-epithiobutane, suggesting a role for the epithio group in the nephrotoxicity of these nitriles. The relatively low SCN- excretion in CEB-treated rats also suggested that cyanide played only a minimal role in CEB toxicity, while the high SCN- excretion, clinical signs of cyanide poisoning and lack of histological changes imply a greater role for metabolically-derived cyanide in VN toxicity. The enhancement of tissue RSH by CEB treatment with indications of enhanced tissue glutathione concentrations suggested the involvement of glutathione in the detoxication of CEB and/or its reactive metabolites.

Selective pancreato-toxicity in the rat induced by the naturally occurring plant nitrile 1-cyano-2-hydroxy-3-butene.

The acute toxicity of 1-cyano-2-hydroxy-3-butene (CHB), a nitrile derived from many cruciferous plants, was investigated. Young male CDF (F-344/CrlBr) rats were treated by gavage once daily with 200 mg (2.1 mmol) CHB/kg body weight for 0-4 days and killed 24 hr after the final dose. Lesions were confined to the exocrine pancreas and characterized by individual acinar cell death, inflammation and acinar atrophy and disorganization. Ultrastructural alterations included dilation of cisternae of the acinar cell endoplasmic reticulum, acinar cell death resembling apoptosis, macrophage phagocytosis of acinar cell debris and regenerative changes in remaining acinar cells. Pancreatic, hepatic and renal non-protein thiol concentrations were elevated, suggesting an enhancement of tissue glutathione concentrations and an alteration in glutathione metabolism. Urinary thiocyanate (SCN-) excretion was modestly elevated, indicating some in vivo cyanide release from this nitrile. The results of this study indicate that CHB is a selective pancreatotoxin, inducing changes consistent with apoptosis. CHB is also a possible inducer of tissue glutathione in the liver and kidneys as well as in the pancreas, even at toxic doses.