Comparison of the Induction Profile of Hepatic Drug-metabolizing Enzymes Between Piperonyl Butoxide and Phenobarbital in Rats.

Watanabe, Toshiyuki; Manabe, Sunao; Ohashi, Yoshihiko; Okamiya, Hideaki; Oda, Hiroshi; Mitsumori, Kunitoshi

doi:10.1293/tox.11.1

Cited by 17 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), with the intensity of the lesions exhibiting an apparent time dependence. Previous reports indicate that both PBO and PhB have the ability to cause hepatocyte hypertrophy through induction of several CYP subfamilies, (19,23,29) and the present results are consistent with such findings. mRNA levels of Cyp 2B1 showed time-dependent increases upon PBO or PhB exposure, while increased mRNA levels of Cyps 1A1 and 1A2 were induced only by PBO.…”

Section: Resultssupporting

confidence: 93%

“…(22) An understanding of whether CYP-inducers lacking genotoxicity but still showing hepatocarcinogenicity can impact DNA integrity via generation of reactive oxygen species, and consequently induce various mutations, is critical for comprehending the actual risk of these compounds to humans. In the present study, we have examined piperonyl butoxide (PBO) and phenobarbital (PhB), both of which can induce several types of CYP, (23) as well as hepatocellular tumor formation in the 4 To whom correspondence should be addressed. …”

mentioning

confidence: 99%

See 1 more Smart Citation

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

et al. 2010

View full text Add to dashboard Cite

Previous reports have proposed that reactive oxygen species resulting from induction of cytochrome P450 (CYP) isozymes might be involved in the modes of action of hepatocarcinogens with CYP-inducible potency. In the present study, we investigated 8-hydroxydeoxyguanosine (8-OHdG) levels, in vivo mutagenicity and glutathione S-transferase placental form (GST-P)-positive foci in the livers of gpt delta rats treated with piperonyl butoxide (PBO) or phenobarbital (PhB) for 4 and 13 weeks. Significant elevations in Cyp 1A1 and Cyp 1A2 mRNA levels after PBO treatment, and in Cyp 2B1 mRNA levels after PBO or PhB treatment, appeared together with remarkable hepatomegaly through the experimental period. Time-dependent and statistically significant increases in 8-OHdG levels were observed in the PBO treatment group along with significant increases in proliferating cell nuclear antigen (PCNA)-positive hepatocytes at 4 weeks, while no increase in 8-OHdG levels was found in PhB-treated rats. No changes in mutant frequencies of gpt and red/gam (Spi -) genes in liver DNA from PBO-or PhB-treated rats were observed at 4 or 13 weeks. A 13-week exposure to either PBO or PhB did not affect the number and area of GST-P-positive hepatocytes. CYP 1A1 and 1A2 induction may be responsible for elevated levels of 8-OHdG in PBO-treated rats. However, neither GC:TA transversions nor deletion mutations, typically regarded as 8-OHdG-related mutations, were observed in any of the treated rats. We conclude that reactive oxygen species, possibly produced through CYP catalytic pathways, likely induced genomic DNA damage but did not give rise to permanent gene mutation. (Cancer Sci 2010; 101: 2525-2530 O xidative stress induces cell proliferation due to either activation of various transcriptional genes related to the cell cycle or to site-specific toxicity. As such, oxidative stress may take part in non-genotoxic carcinogenesis.(1,2) Exposure to exogenous chemicals are able to yield oxidative stress in the body by various ways such as their oxidizing properties, (3) production of radicals through a redox cycle in their metabolism, (4) depletion of glutathione resulting from utilization for their conjugation, (5) and their cytochrome P450 (CYP)-mediated metabolizing pathways.(6) All of these mechanisms for generating oxidative stress are characterized by having site specificity. In addition, all of the above cases except oxidizing properties require in vivo metabolism to produce oxidative stress, which may be the major reason why such chemicals fail to show genotoxicity in conventional mutagenicity tests. The CYP act on a wide variety of chemicals, and CYP involvement in the production of reactive oxygen species during substrate oxidation is well documented.(7-9) However, since the amount of free radicals generated through the normal catalytic cycle is small, (10) induction of CYP might be necessary for any associated oxidative properties to play a role in carcinogenesis in vivo. Various chemicals with CYP-inducible properties demonstrate hepatocar...

show abstract

Section: Resultssupporting

confidence: 93%

mentioning

confidence: 99%

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Recent work by Watanabe et al (1998) in the rat is in agreement with these findings of Phillips. These workers also noted weak induction of the CYP4A isozyme.…”

Section: Mode Of Action Considerations For Oncogenicitysupporting

confidence: 86%

The Safety Assessment of Piperonyl Butoxide

Osimitz

2010

Hayes' Handbook of Pesticide Toxicology

View full text Add to dashboard Cite

“…In the induction of liver hypertrophy, PBO increases expression of liver metabolizing enzymes such as CYP1A1, 1A2, 2B1/2, 3A and 4A in rats Watanabe et al, 1998;Tasaki et al, 2010;Morita et al, 2013) and CYP1A1, 1A2 and 2B10 in mice. Among them, CYP1A1 induction in mice was reported to be mediated by the aryl hydrocarbon receptor activation (Adams et al, 1993;Ryu et al, 1996;Muguruma et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide

et al. 2015

View full text Add to dashboard Cite

-Nuclear receptors play important roles in chemically induced liver hypertrophy in rodents. To clarify the involvement of constitutive androstane receptor (CAR) and other nuclear receptors in mouse liver hypertrophy induced by different doses of piperonyl butoxide (PBO), wild-type and CARknockout mice were administered PBO (200, 1,000, or 5,000 ppm) in the basal diet for 1 week. Increased liver weight and diffuse hepatocellular hypertrophy were observed at 5,000 ppm for both genotypes, accompanied by increased Cyp3a11 mRNA and CYP3A protein expression, suggesting that CAR-independent pathway, possibly pregnane X receptor (PXR), plays a major role in the induction of hypertrophy. Moreover, wild-type mice at 5,000 ppm showed enhanced hepatocellular hypertrophy and strong positive staining for CYP2B in the centrilobular area, suggesting the localized contribution of CAR. At 1,000 ppm, only wild-type mice showed liver weight increase and centrilobular hepatocellular hypertrophy concurrent with elevated Cyp2b10 mRNA expression and strong CYP2B staining, indicating that CAR was essential at 1,000 ppm. We concluded that high-dose PBO induced hypertrophy via CAR and another pathway, while lower dose of PBO induced a pathway mediated predominantly by CAR. The dose-responsiveness on liver hypertrophy is important for understanding the involvement of nuclear receptors.

show abstract

Comparison of the Induction Profile of Hepatic Drug-metabolizing Enzymes Between Piperonyl Butoxide and Phenobarbital in Rats.

Cited by 17 publications

References 36 publications

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

The Safety Assessment of Piperonyl Butoxide

Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide

Contact Info

Product

Resources

About