Modulation of Kupffer cells on hepatic drug metabolism

Table 1 Influence of different dose of GdCl₃ on P450 content and P450 isoform activities

Group	P-450 (nmol/mg·pro)	NADPH-C (nmol/min·mg·pro)	ANH (nmol/min·mg·pro)	AMD (nmol/min·mg·pro)	EMD (nmol/min·mg·pro)
Control	1.4 ± 0.4	14.5 ± 2.8	0.038 ± 0.009	0.96 ± 0.07	0.89 ± 0.06
GdCl310-1 d	1.13 ± 0.25	10.9 ± 1.0b	0.032 ± 0.016	0.76 ± 0.07b	0.78 ± 0.12
GdCl320-1 d	0.87 ± 0.28b	10.5 ± 1.8b	0.033 ± 0.006	0.82 ± 0.03a	0.74 ± 0.13a
GdCl340-1 d	1.01 ± 0.29a	6.0 ± 1.0b	0.036 ± 0.010	0.77 ± 0.17a	0.74 ± 0.18a

GdCl₃10-1 d, GdCl₃20-1 d, GdCl₃40-1 d: Mice were intraperitoneally injected with GdCl₃ 10, 20, 40 mg/kg, respectively, and sacrificed after 1 d. The hepatic microsome was prepared to assess the content of P450 and the activities of P450 isoforms. P450: cytochrome P450; NADPH-C: NADPH-cytochrome c reductase; ANH: aniline hydroxylase; AMD: aminopytine N-demethylase; EMD: erythomycin N-demethylase (n = 8, mean ± SD,

^aP < 0.05,

^bP < 0.01 compared with control group).

Table 2 Time course of alterations of P450 content, activities of P450 isoforms, S9-GSTpi, S9-GST and mGST by Kupffer cell blockade

Group	Control	GdCl320-1 d	GdCl320-3 d	GdCl320-6 d
P-450 (nmol/mg·pro)	1.4 ± 0.4	0.87 ± 0.28b	0.90 ± 0.21b	0.59 ± 0.24b
NADPH-C (nmol/min·mg·pro)	14.5 ± 2.8	10.5 ± 1.8b	7.2 ± 1.0b	6.1 ± 0.8b
ANH (nmol/min·mg·pro)	0.038 ± 0.009	0.033 ± 0.006	0.024 ± 0.006b	0.024 ± 0.006b
AMD (nmol/min·mg·pro)	0.96 ± 0.07	0.82 ± 0.03a	1.31 ± 0.24b	1.31 ± 0.24b
EMD (nmol/min·mg·pro)	0.89 ± 0.06	0.74 ± 0.13a	1.53 ± 0.26b	2.5 ± 0.3b
S9-GSTpi (nmol/min·mg·pro)	1.07 ± 0.28	0.93 ± 0.17	1.1 ± 0.4	0.98 ± 0.23
S9-GST (nmol/min·mg·pro)	8.3 ± 0.91	0.2 ± 1.5a	11.4 ± 0.9b	11.1 ± 1.3b
mGST (nmol/min·mg·pro)	0.25 ± 0.03	0.28 ± 0.06	0.31 ± 0.04b	0.305 ± 0.015b

GdCl₃20-1 d, GdCl₃20-3 d, GdCl₃20-6 d: Mice were intraperitoneally injected with a signal dose of 20 mg/kg of GdCl_{3 ,} and sacrificed after 1 d, 3 d, and 6 d of GdCl₃ treatment. The hepatic microsome was prepared to assay the P450 content, and activities of P450 isoforms, S9-GSTpi, S9-GST and mGST (n = 8, mean ± SD,

^aP < 0.05,

^bP < 0.01 compared with control group).

Table 3 Influence of ASP on P450 content, P450 isoform activities and activities of S9-GSTpi, S9-GST and mGST

Group	Control	ASP1	ASP2	ASP3
P-450 (nmol/mg·pro)	1.4 ± 0.4	2.1 ± 0.4b	1.2 ± 0.4	0.60 ± 0.13b
NADPH-C (nmol/min·mg·pro)	14.5 ± 2.8	19.7 ± 2.2b	19.1 ± 4.3a	7.6 ± 1.1b
ANH (nmol/min·mg·pro)	0.038 ± 0.009	0.045 ± 0.009b	0.018 ± 0.006b	0.010 ± 0.003b
AMD (nmol/min·mg·pro)	0.96 ± 0.07	1.29 ± 0.11b	1.11 ± 0.19	0.61 ± 0.16b
EMD (nmol/min·mg·pro)	0.89 ± 0.06	1.30 ± 0.21	1.14 ± 0.33	0.41 ± 0.09b
S9-GSTpi (nmol/min·mg·pro)	1.07 ± 0.28	1.2 ± 0.3	1.15 ± 0.26	0.78 ± 0.19a
S9-GST (nmol/min·mg·pro)	8.3 ± 0.9	0.5 ± 1.9a	11.8 ± 1.5a	7.9 ± 0.7a
mGST (nmol/min·mg·pro)	0.25 ± 0.03	0.29 ± 0.03a	0.35 ± 0.08b	0.155 ± 0.016b

ASP1, ASP2, ASP3: Mice were given 30, 60, and 120 mg/kg ASP, ig, qd × 7 d, respectively and sacrificed on day 7. The hepatic microsome was prepared to assay the content of P450, and activities of P450 isoforms, S9-GSTpi, S9-GST and mGST. (n = 8, mean ± SD,

^aP < 0.05,

^bP < 0.01 compared with control group).

Table 4 Influence of different dose of GdCl₃ on activities of S9-GSTpi, S9-GST and mGST

Group	S9-GSTpi	S9-GST (nmol/min·mg·pro)	mGST
Control	1.07 ± 0.28	8.3 ± 0.9	0.25 ± 0.03
GdCl310-1d	1.16 ± 0.0.19	9.8 ± 1.5a	0.289 ± 0.026a
GdCl320-1d	0.93 ± 0.17	10.2 ± 1.5a	0.28 ± 0.06
GdCl340-1d	0.91 ± 0.12	7.9 ± 0.8	0.264 ± 0.012

The administration of GdCl₃ and the treatment of animals were the same as described in Table 1. S9-GST: glutathione s-trans-ferase in S9; S9-GSTpi: glutathione s-transferase pi in S9; mGST: glutathione s-transferase in microsome (n = 8, mean ± SD,

^aP < 0.05 compared with control group).