Mechanisms of liver injury and tissue repair in thioacetamide hepatotoxicity following diet restriction

The objective of these experiments was to investigate the effect of diet restriction (DR) in male Sprague-Dawley rats (250–275 g) on liver injury of a model hepatotoxicant (thioacetamide, TA) and the final outcome of that injury. A DR of 35% for 21 days was chosen for all the studies. Ad libitum (AL) fed rats were used as controls. A >6-fold higher liver injury was evident in DR rats as compared to AL rats following TA (50 mg/kg, ip) administration. However, in DR rats the number of cells progressing through the various phases of the cell cycle was ∼ 4-fold higher than in AL rats. Surprisingly, DR resulted in 70% survival as compared to only 10% survival in the ad libitum group following lethal dose administration. The mechanism that allows the DR rats to escape mortality was investigated.;The time course of liver injury and liver tissue repair was investigated in AL and DR rats at the same lethal dose (600 mg TA/kg, ip) used in the above studies. Peak liver injury was ∼ 2-fold higher in DR rats as compared to that seen in AL rats. However, temporal changes and higher tissue repair in DR rats appear to allow a significant number of DR rats to escape the lethal consequence.;Is higher compensatory tissue repair observed in the DR rats simply because of higher liver injury? Equitoxic dose experiments revealed that despite equal liver injury in DR and AL rats, the compensatory tissue repair is much higher and appears on time following DR. Therefore, difference in lethality is due to a prompt and higher tissue repair response in DR rats, presumably related to the acquired physiological homeostasis in DR rats.;In order to explore the molecular events for highly stimulated tissue repair response in DR rats, EGFr mRNA levels and signal transduction events (EGFr tyrosine phosphorylation and EGFr density) were measured during a time course (0–24) hr after TA administration. There was a significant increase in EGFr mRNA levels at 12 hr following TA administration in the DR rats which declined to control levels by 24 hr. AL rats did not show any significant increase in the EGFr mRNA levels. However, EGFr tyrosine phosphorylation and total EGFr density levels were unaltered in DR rats. Additionally, DR significantly increased apoptosis at 24 hr following TA administration, possibly contributing to the efficiency of time repair response. However, other possibilities for enhanced tissue repair response remain to be investigated.;What is the reason for increased mechanism-based liver injury of TA in DR rats? DR resulted in increased total cytochrome P450 (CYP450) content as well as Mold increase in cytochrome P450 2E1 (CYP2E1) activity as measured by chlorzoxazone hydroxylation. Further verification of the involvement of CYP2E1 in TA bioactivation was assessed by CYP2E1 induction studies employing pyridine (PYR) and isoniazid (INZ) and CYP2E1 inhibition studies with diallyl sulfide (DAS). These findings confirm predominant involvement of CYP2E1 in mechanism-based liver injury of TA.;In spite of a wealth of published literature in the area of DR, the effect of DR on acute chemical toxicities has remained uninvestigated. Findings from this study suggest that DR has the potential to protect from life-threatening exposure and severe toxic injury. Additionally, the findings vividly point to a separation of the mechanisms of tissue injury from biological mechanisms such as liver tissue repair. Finally, the findings underscore the desirability of moderate DR as a life-style option, and if practiced, could improve quality of life in addition to accruing savings in burgeoning health care costs.