Localization in the cell cycle of the antimitotic action of the pyrrolizidine alkaloid, lasiocarpine and of its metabolite, dehydroheliotridine

Samuel, A.M.; Jago, Marjorie V.

doi:10.1016/0009-2797(75)90112-x

Cited by 41 publications

(20 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Under these conditions, endogenous hepatocytes do not proliferate and become megalocytic and polyploid. 21,[35][36][37][38] At the same time, normal hepatocytes, transplanted long after RS treatment of the animal, are induced to proliferate and become the predominant hepatic cell type within 1 to 2 months.…”

Section: Discussionmentioning

confidence: 99%

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

et al. 1999

View full text Add to dashboard Cite

Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T 3 ]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T 3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T 3 . Following hepatocyte transplantation and repeated injections of T 3 , the number of transplanted hepatocytes in the liver of RSpretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T 3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T 3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T 3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation. (HEPATOLOGY 1999;30:903-913.)A major problem in most hepatocyte transplantation studies to date has been the limited growth of transplanted cells in the recipient liver. [1][2][3][4][5] Efforts to solve this problem have generally used partial hepatectomy (PH) to remove a portion of the resident liver and thus provide a proliferative stimulus to transplanted cells. [3][4][5] Because host hepatocytes can also respond to this liver-regenerative stimulus, selective repopulation by transplanted cells does not occur under most circumstances. However, PH is not practical for routine use in human hepatocyte transplantation protocols, and thus, establishing alternative methods to stimulate hepatocyte proliferation in the context of cell transplantation is of great interest.Three experimental models of extensive liver repopulation have recently been described: the urokinase-type plasminogen activator (uPA) transgenic mouse, 6-8 the fumarylacetoacetate hydrolase (FAH) null mouse, 9,10 and the retrorsine (RS)/PH-treated rat. 11 In the uPA model, endogenous hepatocytes that have deleted the transgene, 6 or transplanted normal hepatocytes, 7,8 proliferate extensively because of continuous proteolytic destruction of resident hepatocytes expressing uPA. [6][7][8] Similarly, in FAH null mice, transplanted wild-type hepatocytes exhibit a growth advantage over enzymedeficient host cells, because the latter accumulate toxic intermedia...

show abstract

Section: Discussionmentioning

confidence: 99%

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

et al. 1999

View full text Add to dashboard Cite

show abstract

“…[22][23][24][25] Although pyrrolizidine alkaloids are metabolized rapidly, their effect on hepatocyte proliferation lasts for weeks to months. [22][23][24][25]34,35 In this regard, we previously reported that transplantation of normal hepatocytes into the liver of rats treated with lasiocarpine, a related pyrrolizidine alkaloid, resulted in almost complete normalization of liver histology at 3 months posttransplantation. 35 This suggested that transplanted normal cells may Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Long-Term, Near-Total Liver Replacement by Transplantation of Isolated Hepatocytes in Rats Treated with Retrorsine

Laconi

Oren

Mukhopadhyay

et al. 1998

The American Journal of Pathology

362

401

View full text Add to dashboard Cite

Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV؉ Fischer 344 rats were transplanted into the liver of DPPIV ؊ mutant Fischer 344 rats after a combined treatment with retrorsine , a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats , clusters of proliferated DPPIV ؉ hepatocytes containing 20 to 50 cells/cluster , mostly derived from single transplanted cells , were evident at 2 weeks , increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year , the duration of experiments conducted. In male rats , liver replacement occurred more rapidly and was more extensive , with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks , 40 to 50% at 1 month , 90 to 95% at 2 months , 98% at 4 months , and 99% at 9 months.

show abstract

“…The block imposed by pyrrolizidine alkaloids, including RS, has long been associated to the G2-M phases of the cell cycle [6,7]. This was mostly based on the presence of enlarged hepatocytes (megalocytes) in the liver exposed to these naturally occurring chemicals [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Cyclin D1 is up-regulated in hepatocytes in vivo following cell-cycle block induced by retrorsine

Pitzalis¹,

Doratiotto²,

Greco³

et al. 2005

Journal of Hepatology

View full text Add to dashboard Cite

Localization in the cell cycle of the antimitotic action of the pyrrolizidine alkaloid, lasiocarpine and of its metabolite, dehydroheliotridine

Cited by 41 publications

References 20 publications

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Long-Term, Near-Total Liver Replacement by Transplantation of Isolated Hepatocytes in Rats Treated with Retrorsine

Cyclin D1 is up-regulated in hepatocytes in vivo following cell-cycle block induced by retrorsine

Contact Info

Product

Resources

About