Interleukin 8 production of human leukocytes stimulated by triple or single helical conformer of an antitumor (1→3)‐β‐D‐glucan preparation,sonifilan

Previous research has suggested that the immunopharmacological activity of soluble (1→3)‐β‐D‐glucan in mice depends on its conformation. In the present study, we examined the relationship between conformation of Sonifilan (SPG), a high molecular weight (1→3)‐β‐D‐glucan, and interleukin 8 (IL‐8) productivity in an in vitro human system. All experiments were performed using a polypropylene tube in order to reduce cellular adherence and reduce integrin‐mediated signaling. SPG takes the form of a triple helical conformer in water, which changes in response to treatment with an aqueous sodium hydroxide to a single helical conformer (SPG‐OH). Whole blood, peripheral blood mononuclear cells (PBMC), and neutrophils (PMN) were stimulated with either SPG or SPG‐OH and then cultured in vitro. Next, IL‐8 production of the cells and supernatants was measured immunochemically (ELISA and FACS). In whole blood and PBMC cultures, SPG‐OH induced higher IL‐8 production than SPG. In PMN culture, IL‐8 production induced by SPG was comparable to that of SPG‐OH. Enhanced IL‐8 production of monocytes and PMN was confirmed by detection of increased levels of intracellular IL‐8 cultured in the presence of blefeldin and then assessed by FACS. These findings suggested that SPG and SPG‐OH enhanced the productivity of IL‐8 in human leukocytes. Drug Dev. Res. 48:17–25, 1999. © 1999 Wiley‐Liss, Inc.     

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary‐butyl ether (ETBE), caused liver tumors in male rats, while tertiary‐butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary‐butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat‐specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC_0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male‐rat‐specific mode of action for TBA‐induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC_0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd