Metabolism by the intestinal microbiota might result in a different metabolite profile than that produced by host tissues. This could potentially result in either activation or inactivation of the pharmacological and/or toxicological actions of the compound in question. The contribution of the intestinal microbiota to drug metabolism remains relatively unexplored. Therefore, studies of xenobiotic metabolism by the intestinal microbiota need to be included in new drug development as well as classical studies of host tissue metabolism.
The hepatotoxic effects of 1-bromopropane (1-BP) and its conjugation with glutathione were investigated in male ICR mice. A single dose (1000 mg/kg, po) of 1-BP in corn oil to mice significantly increased serum activities of alanine aminotransferase and aspartate aminotransferase. Glutathione (GSH) content was dose-dependently reduced in liver homogenates 12 h after 1-BP treatment. In addition, 1-BP treatment dose-dependently increased levels of S-propyl GSH conjugate at 12 h after treatment, as measured by liquid chromatography-electrospray ionization tandem mass spectrometry. The GSH conjugate was maximally increased in liver at 6 h after 1-BP treatment (1000 mg/kg), with a parallel depletion of hepatic GSH content. Finally, 1-BP induced the production of malondialdehyde in liver. The present results suggest that 1-BP might cause hepatotoxicity, including lipid peroxidation via the depletion of GSH, due to the formation of GSH conjugates in male ICR mice.
Role of metabolism by intestinal bacteria in arbutin-induced immunotoxicity was investigated in splenocyte cultures. Following an incubation of arbutin with 5 different intestinal bacteria for 24 hr, its aglycone hydroquinone could be produced and detected in the bacterial culture media with different amounts. Toxic effects of activated arbutin by intestinal bacteria on lymphoproliferative response were tested in splenocyte cultures from normal mice. Lipopolysaccharide and concanavalin A were used as mitogens for B- and T-cells, respectively. When bacteria cultured medium with arbutin was treated into the splenocytes for 3 days, the medium cultured with bacteria producing large amounts of hydroquinone induced suppression of lymphoproliferative responses, indicating that metabolic activation by intestinal bacteria might be required in arbutin-induced toxicity. The results indicated that the present testing system might be applied for determining the possible role of metabolism by intestinal bacteria in certain chemical-induced immunotoxicity in animal cell cultures.
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