Regenerative changes in hepatic morphology and enhanced expression of CYP2B10 and CYP3A during daily administration of cocaine

Abstract

The effects of daily cocaine administration for up to 14 days were studied in terms of hepatic morphology and the expression of cytochrome P450 (CYP) enzymes in the mouse liver. Daily intraperitoneal doses of 60 mg/kg of cocaine for 3 days induced severe hepatocellular necrosis in the pericentral zone and decreased activities of CYP1A2, CYP2A4/5, and CYP2Cx. The microsomal CYP2B10 protein content was increased by about 2.5-fold, but 2B10-dependent 7-pentoxyresorufin O-dealkylase (PROD) activity was barely detectable. Five or seven daily cocaine doses caused prominent pericentral inflammation and a significant (up to 14-fold) increase in the microsomal protein content and PROD activity. An increase in microsomal CYP3A was also evident, but CYP2A5 and CYP1A2 still remained at a low level. Immunohistochemical examination showed that the relative induction of CYP2B10 and CYP3A after treatment with cocaine was strongest in perivenous hepatocytes. Immunoinhibition experiments showed that CYP2B10 accounted for catalysis of only 15% to 20% of the enhanced microsomal cocaine N-demethylase (CNDM) activity, which correlated well with immunoreactive 3A protein, and could be blocked 70% to 90% by triacetyloleandomycin. After 10 or 14 daily doses of cocaine, regenerative changes with hepatocyte ballooning were observed, coinciding with increases in CYP1A2, CYP2A4/5, and CYP3A. These results suggest the following: (1) cocaine enhances its own cytochrome P450-dependent metabolism; (2) increased production of norcocaine in microsomes is catalyzed mainly by CYP3A enzyme(s), whereas 2B10, although markedly increased by cocaine treatment, has only a minor role in cocaine hepatotoxicity; and (3) despite increased microsomal CNDM activity, cocaine-induced liver injury is reversible in mice.

Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

“…Monoclonal CYP2E1 (1-98-1) and CYP3A2 (2-13-1) antibodies were used for the detection of CYP2E1 and CYP3A. 17,22 A previously described chicken anti-CYP2A antibody was used for the detection of CYP2A. 17 Liver Histology and Immunohistochemistry.…”

“…[13][14][15][16] CYP2A induction by ethanol has not been previously examined, whereas both CYP2A and CYP3A have been shown to increase in mice with cocaine-induced liver disease. 17 The present work was designed to compare the appearance and hepatocellular distribution of various aldehyde-protein adducts and CYP2E1, CYP2A, and CYP3A enzymes by immunohistochemistry of liver samples harvested from micropigs fed ethanol for 12 months. Because the susceptibility for the development of alcohol-induced liver disease is known to differ between males and females, the present experiments were performed in both castrated and noncastrated male micropigs and the results were correlated with serum testosterone and 17-␤-estradiol (17-␤-EST) hormone levels at the time of terminal liver biopsy.…”

Hepatotoxicity of psychotropic drugs

“…In naive mice, coagulative necrosis is localized to the midzonal or the centrilobular zone depending on the strain. [47][48][49] In mice pretreated with phenobarbital, the toxicity is increased and shifts to the periportal zone. 48,49 ␤-Naphthoflavone and chronic ethanol pretreatment produce sharply localized centrilobular damage and increased liver injury.…”

“…47 Norcocaine nitroxide, when administered to mice, induces hepatotoxicity that is P450-dependent and morphologically identical to that of the parent compound, 55 including the fact that pretreatment of animals with phenobarbital shifts the zone of injury from midzonal to periportal. Thus, this sheds no light on whether the injury mechanism involves redox cycling oxidative stress or covalent binding of a toxic metabolite (Fig.…”

Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma

“…Studies on CYP2A5, the mouse orthologue of CYP2A6, have revealed that it is inducible by a variety of structurally dissimilar compounds, including phenobarbital, some heavy metals, heterocyclic nitrogen-containing agents, and various hepatotoxins including cocaine. 3,15,16 Animal studies have also shown that the expression of hepatic CYP2As is up-regulated by various types of biological insults, such as infestation with the liver fluke Opisthorchiasis viverrini 17 and integration of hepatitis B virus (HBV) to hepatocyte DNA. 18 In these animal models, CYP2A induction is associated with chronic inflammation in the liver tissue.…”