Modulation of Kupffer cells on hepatic drug metabolism.
OBJECTIVE
To observe the effects of Kupffer cells on hepatic drug metabolic enzymes.


METHODS
Kunming mice were i.p. injected with GdCl310, 20, 40 mg/kg to decrease the number and block the function of kupffer cells selectively. The contents of drug metabolic enzymes, cytochrome P450, NADPH-cytochrom C redutase (NADPH-C), aniline hydroxylase (ANH), aminopyrine N-demethylase (AMD), erythromycin N-demethylase (EMD), and glutathione s-transferase (mGST) in hepatic microsome and S9-GSTpi, S9-GST in supernatant of 9 000 g were accessed 1 d after the injection. The time course of alteration of drug metabolic enzymes was observed on d 1, 3, and 6 treated with a single dose GdCl3. Mice were treated with Angelica sinensis polysaccharides (ASP) of 30, 60, 120 mg/kg, i.g., qd x 6 d, respectively and the same assays were performed.


RESULTS
P450 content and NADPH-C, ANH, AMD, and EMD activities were obviously reduced 1 d after Kupffer cell blockade. However, mGST and S9-GST activities were significantly increased. But no relationship was observed between GdCl3 dosage and enzyme activities. With single dose GdCl3 treatment, P450 content, NADPH-C, and ANH activities were further decreased following Kupffer cell blockade lasted for 6 d, by 35.7%, 50.3%, 36.5% after 3 d, and 57.9%, 57.9%, 63.2% after 6 d, respectively. On the contrary, AMD, EMD, mGST, and S9-GST activities were raised by 36.5%, 71.9%, 23.1%, 35.7% after 3 d, and 155%, 182%, 21.5%, 33.7% after 6 d, respectively. Furthermore, the activities of drug metabolic enzymes were markedly increased after 30 mg/kg ASP treatment, and decreased significantly after 120 mg/kg ASP treatment. No change in activity of S9-GSTpi was observed in the present study.


CONCLUSIONS
Kupffer cells play an important role in the modulation of drug metabolic enzymes. The changes of drug metabolic enzyme activities depend on the time of kupffer cell blockade and on the degree of Kupffer cells activated. A low concentration of ASP increases the activities of drug metabolic enzymes, but a high concentration of ASP decreases the activities of drug metabolic enzymes.
Ding
Hong
H
Medical College, Shantou University, Guangdong Province, China.
Tong
Jing
J
Wu
Shi-Cheng
SC
Yin
Deng-Ke
DK
Yuan
Xian-Fen
XF
Wu
Jian-Yuan
JY
Chen
Jun
J
Shi
Gang-Gang
GG
D029971:Angelica sinensis; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism
D004365:Drugs, Chinese Herbal; D007527:Isoenzymes; D005682:Gadolinium; C044613:angelicae sinensis extract; C038958:gadolinium chloride