PMID- 23665940
OWN - NLM
STAT- MEDLINE
DCOM- 20131023
LR  - 20190911
IS  - 1880-3989 (Electronic)
IS  - 0388-1350 (Linking)
VI  - 38
IP  - 3
DP  - 2013
TI  - Enhanced liver tumor promotion activity in rats subjected to combined 
      administration of phenobarbital and orphenadrine.
PG  - 415-24
AB  - Phenobarbital (PB) and orphenadrine (ORPH) are cytochrome P450 (CYP) 2B inducers 
      and have liver tumor-promoting effects in rats. In this study, we performed a rat 
      two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of 
      PB and ORPH co-administration. Twelve male rats per group were given an 
      intraperitoneal injection of N-diethylnitrosamine (DEN) for initiation. Two-week 
      after DEN administration, rats were given PB (60 or 120 ppm in drinking water), 
      ORPH (750 or 1,500 ppm in diet) or 60 ppm PB+750 ppm ORPH for 6-week. One-week 
      after the PB/ORPH treatment, all rats were subjected to two-thirds partial 
      hepatectomy. To evaluate the effect of the combined administration, we used two 
      statistical models: a heteroadditive model and an isoadditive model. In the 
      heteroadditive model, the net values of the number and area of glutathione 
      S-transferase placental form (GST-P) positive foci, Cyp2b1/2, Gstm3 and Gpx2 mRNA 
      levels, microsomal reactive oxygen species (ROS) production and thiobarbituric 
      acid-reactive substances level in the PB+ORPH group were significantly higher 
      than the sum of the net values of those in the Low PB and Low ORPH groups. In the 
      isoadditive model, the average values of the area of GST-P positive foci and PCNA 
      positive hepatocyte ratio and Gstm3 mRNA level in the PB+ORPH group were 
      significantly higher than the average values of those in the High PB and High 
      ORPH groups. These results suggest that PB and ORPH co-administration causes 
      synergistic effects in liver tumor-promoting activity in rats resulting from 
      oxidative stress due to enhanced microsomal ROS production.
FAU - Morita, Reiko
AU  - Morita R
AD  - Laboratory of Veterinary Pathology, Tokyo University of Agriculture and 
      Technology, Japan. rmorita@cc.tuat.ac.jp
FAU - Yafune, Atsunori
AU  - Yafune A
FAU - Shiraki, Ayako
AU  - Shiraki A
FAU - Itahashi, Megu
AU  - Itahashi M
FAU - Akane, Hirotoshi
AU  - Akane H
FAU - Nakane, Fumiyuki
AU  - Nakane F
FAU - Suzuki, Kazuhiko
AU  - Suzuki K
FAU - Shibutani, Makoto
AU  - Shibutani M
FAU - Mitsumori, Kunitoshi
AU  - Mitsumori K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - J Toxicol Sci
JT  - The Journal of toxicological sciences
JID - 7805798
RN  - 0 (Drug Combinations)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Thiobarbituric Acid Reactive Substances)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - AL805O9OG9 (Orphenadrine)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2B1)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - Cytochrome P-450 CYP2B1/metabolism
MH  - Diethylnitrosamine/administration & dosage/toxicity
MH  - Drug Combinations
MH  - Drug Synergism
MH  - Enzyme Induction/drug effects
MH  - Liver Neoplasms/*chemically induced
MH  - Male
MH  - Microsomes, Liver/metabolism
MH  - Orphenadrine/administration & dosage/*toxicity
MH  - Oxidative Stress/genetics
MH  - Phenobarbital/administration & dosage/*toxicity
MH  - Rats
MH  - Rats, Inbred F344
MH  - Reactive Oxygen Species/metabolism
MH  - Thiobarbituric Acid Reactive Substances/metabolism
EDAT- 2013/05/15 06:00
MHDA- 2013/10/24 06:00
CRDT- 2013/05/14 06:00
PHST- 2013/05/14 06:00 [entrez]
PHST- 2013/05/15 06:00 [pubmed]
PHST- 2013/10/24 06:00 [medline]
AID - DN/JST.JSTAGE/jts/38.415 [pii]
AID - 10.2131/jts.38.415 [doi]
PST - ppublish
SO  - J Toxicol Sci. 2013;38(3):415-24. doi: 10.2131/jts.38.415.