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J.Health Sci., 49(4), 292-297, 2003
Effects of Pretreatment of Hep G2 Cells with
beta-Naphthoflavone on Cytotoxicity of Propranolol
and its Active Metabolite 4-Hydroxypropranolol
Junko Miyano,a Harumi
Motoyama,a Masako
Fukuoka,a Shigeo
Yamamoto,b
Shizuo Narimatsu,*, a Kenichiro
Ogura,c Tadashi Watabe,c,
d Masuhiro Nishimura,e
Nobuhiko Ueda,e and Shinsaku
Naitoe
aLaboratories of Health Chemistry and
bBiomolecular Science, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1
Tsushima-naka, Okayama 700-8530, Japan,
cDepartment of Drug Metabolism and Molecular Toxicology, School of Pharmacy,
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan,
dInstitute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan, and
eDivision of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., 115 Kuguhara, Tateiwa, Naruto, Tokushima 772-8601,
Japan
Cytotoxicities of propranolol (PL) and its active metabolite, 4-hydroxypropranolol (4-OH-PL), were
examined in a human hepatoma cell line, Hep G2. Hep G2 cells were cultured in the presence of
beta-naphthoflavone (BNF, 25 or 50 mu M), lansoprazole (LPZ, 25 or 50
mu M) or 0.5% dimethylsulfoxide (vehicle) for 48 hr. The cells
were harvested, and microsomal and cytosolic fractions were prepared by differential centrifugation methods.
Various enzyme activities were determined as follows: microsomal 7-ethoxyresorufin (ER)
O-deethylation as a CYP1A1 index, microsomal phenacetin (PN)
O-deethylation as a CYP1A2 index, microsomal and cytosolic
p-nitrophenyl acetate (NPA) hydrolysis as a carboxylesterase index and cytosolic 4-OH-PL sulfation as a
sulfotransferase index. The pretreatment of Hep G2 cells with LPZ or BNF increased microsomal ER
O-deethylase activities, and the potency of BNF was much higher than that of LPZ. Cytosolic 4-OH-PL sulfation was also
elevated by the pretreatment with BNF but not with LPZ. Microsomal PN
O-deethylase activity was not detectable in either the control or BNF-pretreated group under the conditions used. Microsomal and cytosolic NPA
hydrolase activities were similar between the control and the BNF-pretreated groups. Cytotoxicities of PL and
4-OH-PL were attenuated in BNF-pretreated Hep G2 cells compared to non-pretreated Hep G2 cells. These results
suggest that increased activities of microsomal CYP1A1 and cytosolic sulfotransferases by pretreatment with
BNF may contribute to the attenuating the cytotoxicity of PL and 4-OH-PL in Hep G2 cells, at least in part.
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