Cytochrome P450 2E1 is responsible for the initiation of 1,2-dichloropropane-induced liver damage

Abstract

1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of 1,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of 1,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of 1,2-DCP in mice with or without cytochrome P450 2E1 (CYP2E1) activity. In an in vitro reaction system containing liver homogenate, 1,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e1-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; 1,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor κB p52 pathway was involved in the liver response to 1,2-DCP. Our results clearly indicate that the oxidative metabolism of 1,2-DCP in mice is exclusively catalyzed by CYP2E1, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent.

Acute inhalation co‐exposure to 1,2‐dichloropropane and dichloromethane cause liver damage by inhibiting mitochondrial respiration and defense ability in mice

“…This study demonstrated the hepatotoxic effects of acute inhalation exposure to 1,2‐DCP, DCM and their combination and preliminarily clarified the relative mechanism of 1,2‐DCP and DCM‐induced liver damage. The changes in liver weight, elevated serum transaminase and pathological changes in the liver suggest that 1,2‐DCP produces hepatocellular necrosis and liver damage in mice, and our results are in agreement with previous reports (Cooper, Scott, & Bale, ; Gi et al, 2015b; Yanagiba et al, ).…”

Spontaneous Production of Glutathione‐Conjugated Forms of 1,2‐Dichloropropane: Comparative Study on Metabolic Activation Processes of Dihaloalkanes Associated with Occupational Cholangiocarcinoma

“…This is supported by previous studies reporting the involvement of CYP2E1 in 1,2-DCP metabolism [16, 17], and a dramatic loss of tissue GSH caused by 1,2-DCP administration [18], although the GST gene involved in 1,2-DCP metabolism has not been identified. On the other hand, a part of our previous study, which was conducted in nonphysiological buffer conditions, suggested that GSH could nonenzymatically bind to 1,2-DCP, resulting in GS-Cl-DCP production [12].…”

“…Considering that most dihaloalkanes can be enzymatically activated by either oxidation (cytochrome P450s, CYPs) or by GSH conjugation (glutathione S -transferases, GSTs) [ 6 , 15 ], these two pathways are likely involved in 1,2-DCP metabolism. This is supported by previous studies reporting the involvement of CYP2E1 in 1,2-DCP metabolism [ 16 , 17 ], and a dramatic loss of tissue GSH caused by 1,2-DCP administration [ 18 ], although the GST gene involved in 1,2-DCP metabolism has not been identified. On the other hand, a part of our previous study, which was conducted in nonphysiological buffer conditions, suggested that GSH could nonenzymatically bind to 1,2-DCP, resulting in GS-Cl-DCP production [ 12 ].…”

A trial to find appropriate animal models of dichloropropane‐induced cholangiocarcinoma based on the hepatic distribution of glutathione S‐transferases

“…These results suggest that DCP nephrotoxicity is probably related to mercapturic acid metabolism after oxidation by P450 20) . Another more recent study also argued for the role of cytochrome P450 2E1 in the initiation of DCP-induced liver damage 21) . The present study showed that the distribution of GSTT1 in hamsters was similar to that in humans; that is, GSTT1 was expressed in both the nucleus and cytoplasm of bile duct epithelial cells and some hepatocytes, although our hamsters did not show any specific susceptibility to DCP exposure.…”