Renbin Huang#, Hiroyasu Okuno,
Masashi Takasu, Seiko Takeda,
Haruhiko Kano, Yasuko Shiozaki and Kyoichi Inoue
Third Department of Internal Medicine, Kansai Medical University, Fumizono-cho
10-15, Moriguchi, Osaka 570-8507, Japan
#Presentﾊaddress for correspondence:
Department of Pharmacoloy, Guangxi Medical University, Nanning, Guangxi
530021, P.R. China
Abstract: The present study examined whether rifampin attenuated
glutathione (GSH) depletion by acetaminophen reactive metabolites generated
in the in vitro P450 enzyme system prepared from mouse liver and the possible
mechanism involved in this effect. The results showed that GSH concentration
was decreased concentration-dependently by acetaminophen in the in vitro
P450 enzyme system. Rifampin significantly attenuated acetaminophen-mediated
GSH depletion in a concentration-dependent manner. The concentration-response
curve for GSH depletion of acetaminophen was shifted to the right in a parallel
fashion in the presence of rifampin at the concentration of 3.2ﾊ×ﾊ10-5ﾊM,
which appeared to result from the competitive binding of rifampin to acetaminophen
metabolites. Cytochromeﾊc was markedly reduced by acetaminophen metabolites
in this enzyme system, and GSH concentration-dependently increased the cytochromeﾊc
reduction by acetaminophen metabolites. These findings suggested that cytochromeﾊc
was reduced by the GSH conjugate of acetaminophen metabolites rather than
by acetaminophen-derived superoxide anion (O2
Keywords: Acetaminophen, Rifampin, GSH depletion, Cytochromeﾊc
reduction, P450