Download PDF
Editorial  |  Open Access  |  14 Jul 2015

Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation

Views: 6777 |  Downloads: 813 |  Cited:   0
Hepatoma Res 2015;1:50-1.
Author Information
Article Notes
Cite This Article

It has been shown that preneoplastic liver cell foci and hepatic nodules generated by thioacetamide (TAA) in drug-primed mice, which were first fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate (DDC) or griseofulvin (GF) for 5 months were resistant to protoporphyrin accumulation.[1] DDC or GF are potent porphyrinogenic drugs and accumulate protoporphyrin in the mouse liver. Although DDC or GF are withdrawn for 1 month, when treated with TAA, the nodules formed on the 5th or 7th day of treatment were devoid of protoporphyrin deposits. Feeding DDC or GF for 8 months induced liver tumors which were devoid of protoporphyrin deposits. In contrast, the surrounding liver tissue contained numerous protoporphyrin deposits. This could be attributed to the decreased activity of delta-aminolevulinate synthase, the first rate-limiting enzyme in protoporphyrin synthesis. Furthermore, there could be an increased activity of ferrochelatase, which catalyzes the incorporation of iron into protoporphyrin, and increased activity of heme oxygenase, the last enzyme in porphyrin degradation. Protoporphyrin deposits were found in the normal liver parenchyma, but not in the hyperplastic nodules (HNs) or hepatocellular carcinomas formed in mice fed GF or DDC for 5-12 months.[2-4] C3H male mice, aged 4 weeks (Harlan, Sprague-Dawley, San Diego, CA, USA), were fed a protein-rich 25% semisynthetic complete standard Tekland test diet ad libitum (Tekland, Madison, WI, USA) with 0.1% DDC or 2.5% GF for 1 year and then sacrificed. Control mice were fed the basal diet without DDC. As soon as the mice were killed, their liver was removed. Portions of the liver were fixed in formalin and embedded in paraffin for light microscopic analysis by hematoxylin-eosin and gamma glutamyl transpeptidase (GGT) was accessed by histochemistry. Figure 1 illustrates an HN from a mouse fed DDC for 1 year. The tumor is devoid of protoporphyrin and is surrounded by normal liver parenchyma filled with protoporphyrin deposits. Figure 2 shows hyperplastic foci stained red for GGT, a marker for HN, showing that the precursor lesion is devoid of protoporphyrin deposits. HN or foci are generated during the process of liver cancer development in response to chemical carcinogens or dietary manipulations. HN is a population of cells from which hepatocelluar carcinoma can develop. The HN studied here resembles resistant phenotypes which grow in an otherwise toxic environment of potent porphyrinogenic drugs DDC and GF. The HN is resistant to protoporphyrin accumulation whereas the surrounding normal liver is filled with protoporphyrin. This observation is further supported by the fact that HNs generated by diethylnitrosamine initiation and various promoting regimens are resistant to their own promoting agents. For example, the nodules produced by resistance to a cytotoxicity model using 2-acetyl aminofluorene (2-AAF) are resistant to 2-AAF metabolism.[5] The nodules produced by choline methionine deficient diet are resistant to fat accumulation.[6] The HN nodules generated in orotic acid models are resistant to imbalances of nucleotide pools created by orotic acid;[7] nodules generated in lasiocarpine model are resistant to megalocytic effect of Senecio alkaloid.[8] These selective resistances to cytotoxicity models appear to be precursor lesions for hepatocellular carcinoma development.

Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation

Figure 1. Liver from a mouse fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate for 1 year (×57). Note the hyperplastic nodule is devoid of brown protoporphyrin pigment, whereas the surrounding normal liver parenchyma is filled with protoporphyrin deposits

Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation

Figure 2. Liver from a mouse fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate (DDC) for 5 months, then withdrawn from DDC for 1 month, then refed DDC for 3 days (×567). Note that the hyperplastic nodule stained red for gamma-glutamyl transferase is devoid of protoporphyrin pigment whereas the normal liver parenchyma has numerous protoporphyrin deposits as shown

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

REFERENCES

1. Roomi MW, Gaal K, Yuan QX, French BA, Fu P, Bardag-Gorce F, French SW. Preneoplastic liver cell foci expansion induced by thioacetamide toxicity in drug-primed mice. Exp Mol Pathol 2006;81:8-14.

2. Tazawa J, Irie T, French SW. Mallory body formation runs parallel to gamma-glutamyl transferase induction in hepatocytes of griseofulvin-fed mice. Hepatology 1983;3:989-1001.

3. Oliva J, Bardag-Gorce F, French BA, Li J, McPhaul L, Amidi F, Dedes J, Habibi A, Nguyen S, French SW. Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis. Exp Mol Pathol 2008;84:102-12.

4. Nagao Y, Wan YJ, Yuan QX, Kachi K, Marceau N, French SW. Mouse model of hepatocellular hyperplastic nodule formation characterization of mRNA expression. Hepatol Res 1999;15:110-23.

5. Solt DB, Medline A, Farber E. Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. Am J Pathol 1977;88:595-618.

6. Shinozuka H, Sells MA, Katyal SL, Sell S, Lombardi B. Effects of a choline-devoid diet on the emergence of gamma-glutamyltranspeptidase- positive foci in the liver of carcinogen-treated rats. Cancer Res 1979;39:2515-21.

7. Rao PM, Nagamine Y, Roomi MW, Rajalakshmi S, Sarma DS. Orotic acid, a new promoter for experimental liver carcinogenesis. Toxicol Pathol 1984;12:173-8.

8. Hayes MA, Roberts E, Farber E. Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine. Cancer Res 1985;45:3726-34.

Cite This Article

Export citation file: BibTeX | RIS

OAE Style

French SW, Roomi MW. Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation. Hepatoma Res 2015;1:50-1. http://dx.doi.org/10.4103/2394-5079.155984

AMA Style

French SW, Roomi MW. Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation. Hepatoma Research. 2015; 1: 50-1. http://dx.doi.org/10.4103/2394-5079.155984

Chicago/Turabian Style

French, Samuel W., M. Waheed Roomi. 2015. "Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation" Hepatoma Research. 1: 50-1. http://dx.doi.org/10.4103/2394-5079.155984

ACS Style

French, SW.; Roomi MW. Preneoplastic foci in mice fed diethyl 1, 4-dihydro, 1, 4, 6-trimethyl 3, 5-pyridine decarboxylate are resistant to protoporphyrin accumulation. Hepatoma. Res. 2015, 1, 50-1. http://dx.doi.org/10.4103/2394-5079.155984

About This Article

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which allows others to remix, tweak and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Data & Comments

Data

Views
6777
Downloads
813
Citations
0
Comments
0
0

Comments

Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

0
Download PDF
Cite This Article 1 clicks
Like This Article 0 likes
Share This Article
Scan the QR code for reading!
See Updates
Contents
Figures
Related
Hepatoma Research
ISSN 2454-2520 (Online) 2394-5079 (Print)

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/