A liver DNA synthesis promoter induced in rat plasma by injection of dimethylnitrosamine (DMNA) or thioacetamide

Environ Health Perspect

1995

105

The purpose of the present study was to establish a dose-response relationship for thioacetamide (TA), where tissue regeneration as well as liver injury were two simultaneous but opposing responses. Male Sprague-Dawley rats were injected intraperitioneally with a 12-fold dose range of TA, and both liver injury and tissue repair were measured. Liver injury was assessed by serum enzyme elevations. Serum alanine aminotransferase (ALT) elevation did not show any dose response over a 12-fold dose range up to 24 hr. A dramatic ALT elevation was evident after 24 hr and only for the highest dose (600 mg/kg). Tissue regeneration response was measured by 3H-thymidine (3H-T) incorporation into hepatocellular DNA and by proliferating cell nuclear antigen (PCNA) procedure during a time course (6, 12, 24, 36, 48, 72, and 96 hr). Tissue regeneration, as indicated by 3H-T incorporation, peaked at 36 hr after administration of a low dose of TA (50 mg/kg). With increasing doses, a greater but delayed stimulation of cell division was observed until a threshold was reached (300 mg/kg). Above the tissue repair threshold (600 mg/kg), because stimulated tissue repair as revealed by 3H-T incorporation in hepatonuclear DNA was significantly delayed and attenuated, injury assessed by serum enzyme elevations was remarkably accelerated, indicating unrestrained progression of injury leading to animal death. These findings suggest that, in addition to the magnitude of tissue repair response, the time at which this occurs is critical in restraining the progression of injury, thereby determining the ultimate outcome of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. Figure 2. Figure 3. A Figure 3. B Figure 3. C Figure 3. D Figure 3. E Figure 3. F Figure 4. Figure 5. Figure 6. A Figure 6. B Figure 6. C Figure 7. A Figure 7. B Figure 7. C Figure 7. D Figure 7. E Figure 7. F

mentioning

confidence: 64%

Tissue repair response as a function of dose in thioacetamide hepatotoxicity.

Mangipudy

Chanda

Environ Health Perspect

1995

105

“…Investigations into the mode of action of TA have led to the conclusion that toxicity is dependent on its oxidation in the liver to reactive sulfine metabolites (3). Carnitine, biosynthesized from the essential amino acids lysine and methionine, has been suggested to significantly benefit patients with liver failure (4). L-Carnitine (LC) facilitates entry of long chain fatty acids into mitochondria through acylcarnitine transferase for utilization in energy production (5…”

mentioning

confidence: 99%

Role of nutritional fatty acid and L‐carnitine in the final outcome of thioacetamide hepatotoxicity ¹

Chanda

1994

FASEB j.

Male Sprague-Dawley rats (n = 10/group) were fully protected from a lethal dose (600 mg/kg, i.p.) of thioacetamide by adding 8% (w/w) palmitic acid to the diet and L-carnitine (2 mg/ml) to drinking water for the previous 7 days. Supplements of palmitic acid or L-carnitine alone did not confer protection. Liver injury induced by thioacetamide peaked between 36 and 48 h in both control and supplemented rats. Liver damage regressed thereafter in supplemented rats but progressed in control rats. Immunohistochemical and histopathological observations confirmed biochemical indicators of liver damage. Thus, hepatic tissue repair after thioacetamide-induced tissue injury seems to be stimulated by supplements of fatty acids together with L-carnitine, a mitochondrial transfer agent. The extent to which nutritional supplements may aid in inducing the recovery of liver from injury caused by other hepatotoxic agents remains to be explored.

“…Accordingly, it was reported that the hepatotoxic effects ofTA are manifested only after metabolic conversion to thioacetamide-S-oxide, which undergoes further oxidative metabolism to an as yet unidentified toxic metabolite (7). TA has been reported to stimulate DNA synthesis and mitosis in the liver of rats at doses that produce limited necrosis (9)(10)(11). The rise in DNA synthesis induced by TA has been shown to follow a time course that is similar to that seen following partial hepatectomy (12).…”

mentioning

confidence: 99%

Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

Mangipudy

Rao

Environ Health Perspect

1996

In an earlier study we established that timely and adequate tissue repair response following the administration of a six-fold dose-range of thioacetamide (TA; 50, 150, and 300 mg/kg) prevented progression of injury and led to recovery and animal survival. Delayed and attenuated repair response after the 600 mg/kg TA dose resulted in a marked progression of injury and 100% lethality. The objective of the present study was to further scrutinize this concept in an experimental protocol in which we hypothesized that a selective ablation of the tissue repair response should lead to lethality from the nonlethal, moderately toxic doses of 150 and 300 mg/kg TA. In this study we investigated the effect of the antimitotic agent colchicine (CLC, 1 mg/kg) on the outcome of TA hepatotoxicity. Male Sprague-Dawley rats (175-225 g) were injected intraperitoneally (ip) with 150 and 300 mg/kg TA. We assessed liver injury by serum enzyme elevations and histopathology. Tissue regeneration response was measured by 3H-thymidine incorporation into hepatonuclear DNA and by proliferating cell nuclear antigen (PCNA) assay. S-Phase stimulation, as indicated by 3H-thymidine incorporation, was noted at 36 and 48 hr following the administration of 150 mg/kg TA, whereas with the 300 mg/kg TA S-phase stimulation was elicited at 48 hr following treatment. Therefore, two doses of CLC (30 hr and 42 hr, 1 mg/kg, ip) were administered to the 150 mg/kg treated group while a single dose of CLC (42 hr, 1 mg/kg, ip) was administered to the 300 mg/kg group. CLC treatment resulted in 100% lethality in both groups. Thus, CLC administration converted nonlethal doses into lethal doses. The 150 mg/kg TA dose was then chosen to further investigate the underlying mechanism. Rats treated with TA alone recovered from injury by 36-48 hr while CLC treatment resulted in a progression of injury as indicated by serum enzyme elevation and histopathology. Tissue repair, as evidenced by 3H-thymidine incorporation and PCNA studies explained this dichotomy. Antimitotic intervention with CLC resulted in a significantly diminished repair response leading to unrestrained progression of injury and lethality even from nonlethal doses. This model demonstrates the critical role of tissue repair response in determining the final outcome of toxicity. Images Figure 1. Figure 2. Figure 3. Figure 3. Figure 3. Figure 3. Figure 3. Figure 3. Figure 5. Figure 5. Figure 5. Figure 5. Figure 5. Figure 5. Figure 4. Figure 6.