Attenuation of zinc-induced acute pancreatitis by zinc pretreatment: Dependence on induction of metallothionein synthesis

Pretreatment with zinc (Zn) is known to produce tolerance to several of the toxic effects of heavy metals and pro-oxidants with or without the induction of metallothionein (MT) synthesis. We found previously that injection of high-dose Zn caused acute pancreatitis in mice. An injection of Zn (50-75 mg/kg) resulted in a significant increase in the plasma activities of exocrine enzymes, indicating acute pancreatitis, and no greater increase in Zn concentration in the pancreatic MT fraction with Zn doses. To clarify the role of MT in the pancreatic toxicity of Zn, we examined the effects of pretreatment with nontoxic doses of Zn on the induction of acute pancreatitis by Zn challenge. Pretreatment with Zn (10 mg/kg) 24 hr before Zn challenge attenuated Zn-induced acute pancreatitis. However, pretreatment with Zn only 2 hr before challenge was ineffective. Pretreatment with Zn 24 hr before resulted in more Zn in the NIT fraction of pancreatic cytosol and less Zn in the low-molecular-weight fraction compared with pretreatment 2 hr before. These data indicate that pancreatic MT may diminish the toxicity of Zn by sequestering excess Zn. Moreover, Zn-induced acute pancreatitis also was attenuated by treatment with aprotinin, a trypsin inhibitor. Our findings suggest that the Zn ion - either free or bound to small molecules - is involved in the development of acute pancreatitis that includes intrapancreatic trypsinogen activation.