PMID- 30842367
OWN - NLM
STAT- MEDLINE
DCOM- 20190328
LR  - 20190328
IS  - 1880-3989 (Electronic)
IS  - 0388-1350 (Linking)
VI  - 44
IP  - 3
DP  - 2019
TI  - Effect of the metabolic capacity in rat liver S9 on the positive results of in 
      vitro micronucleus tests.
PG  - 145-153
LID - 10.2131/jts.44.145 [doi]
AB  - A high incidence of positive results is obtained with in vitro genotoxicity 
      tests, which do not correlate with the in vivo negative results in many cases. To 
      address this issue, the metabolic profile of rat liver 9000 x g supernatant 
      fraction (S9) pretreated with phenobarbital (PB) and 5,6-benzoflavone (BNF) was 
      characterized. Furthermore, the in vitro micronucleus tests of 10 compounds were 
      performed with PB-BNF-induced rat S9. PB-BNF increased cytochrome P450 (CYP) 
      activity and CYP1A1, CYP1A2, CYP2B1/2, CYP2C6, CYP3A1, and CYP3A2 expression in 
      rat S9, whereas it decreased CYP2C11 and CYP2E1 expression. PB-BNF-induced S9 
      enhanced the micronucleus induction (MI) of benzo[a]pyrene (BaP), 
      cyclophosphamide (CPA), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 
      hydrochloride (PhIP), which are metabolized by CYP1A1, CYP2C6, and CYP1A2, 
      respectively. In contrast, coumarin and chlorpheniramine showed MI with 
      PB-BNF-induced S9 despite the fact that they show negative results in the in vivo 
      studies. Furthermore, diclofenac, piroxicam, lansoprazole, and caffeine showed MI 
      regardless of the enzyme induction by PB-BNF, whereas phenacetin did not show MI. 
      These results indicate that PB-BNF-induced rat S9 is effective in detecting the 
      genotoxic potential of promutagens, such as BaP, CPA, and PhIP, but not of 
      coumarin and chlorpheniramine, probably due to the differences in the in vitro 
      and in vivo metabolic profile and its exposure levels of the drugs.
FAU - Kishino, Yuki
AU  - Kishino Y
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
FAU - Hasegawa, Tomoko
AU  - Hasegawa T
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
FAU - Arakawa, Shingo
AU  - Arakawa S
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
FAU - Shibaya, Yukari
AU  - Shibaya Y
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
FAU - Yamoto, Takashi
AU  - Yamoto T
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
FAU - Mori, Kazuhiko
AU  - Mori K
AD  - Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - J Toxicol Sci
JT  - The Journal of toxicological sciences
JID - 7805798
RN  - 0 (Mutagens)
RN  - 6051-87-2 (beta-Naphthoflavone)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cricetulus
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - *Micronucleus Tests
MH  - Mutagens/*toxicity
MH  - Phenobarbital/pharmacology
MH  - Rats, Sprague-Dawley
MH  - beta-Naphthoflavone/pharmacology
OTO - NOTNLM
OT  - Cytochrome P450 enzyme
OT  - In vitro micronucleus test
OT  - Inducers
OT  - Metabolic activation system
EDAT- 2019/03/08 06:00
MHDA- 2019/03/29 06:00
CRDT- 2019/03/08 06:00
PHST- 2019/03/08 06:00 [entrez]
PHST- 2019/03/08 06:00 [pubmed]
PHST- 2019/03/29 06:00 [medline]
AID - 10.2131/jts.44.145 [doi]
PST - ppublish
SO  - J Toxicol Sci. 2019;44(3):145-153. doi: 10.2131/jts.44.145.