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

✍ Scribed by P Pellinen; F Stenback; A Kojo; P Honkakoski; H V Gelboin; M Pasanen

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 774 KB
• Volume: 23
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510230316

✦ Synopsis

2B10, although markedly increased by cocaine treat-The effects of daily cocaine administration for up to ment, has only a minor role in cocaine hepatotoxicity; 14 days were studied in terms of hepatic morphology and (3) despite increased microsomal CNDM activity, coand the expression of cytochrome P450 (CYP) enzymes caine-induced liver injury is reversible in mice. (HEPAin the mouse liver. Daily intraperitoneal doses of 60 mg/ TOLOGY 1996;23:515-523.) 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

Cocaine, one of the oldest drugs of abuse, is a natu-CYP2B10 protein content was increased by about 2.5fold, but 2B10-dependent 7-pentoxyresorufin O-dealky-rally occurring plant product found in the leaves of lase (PROD) activity was barely detectable. Five or Erythroxylon coca. In the United States during 1989 seven daily cocaine doses caused prominent pericentral and 1990 cocaine ranked first in both total drug abuse inflammation and a significant (up to 14-fold) increase episodes and in drug-related deaths. 1 The toxicity of in the microsomal protein content and PROD activity. cocaine includes myocardial infarcts, cardiac arrhyth-An increase in microsomal CYP3A was also evident, but mias, and hemorrhage. Psychiatric complications such CYP2A5 and CYP1A2 still remained at a low level. Immuas acute anxiety or panic and paranoid psychosis have nohistochemical examination showed that the relative also been reported. 1,2 induction of CYP2B10 and CYP3A after treatment with One of the most striking toxic effects of cocaine is its cocaine was strongest in perivenous hepatocytes. Immuhepatotoxicity. Cocaine-induced liver injury has been noinhibition experiments showed that CYP2B10 accounted for catalysis of only 15% to 20% of the enhanced documented both in laboratory animals 3,4 and humicrosomal cocaine N-demethylase (CNDM) activity, mans. 5,6 There are marked species differences in the which correlated well with immunoreactive 3A protein, hepatotoxic potency of cocaine, 7 the mouse being the and could be blocked 70% to 90% by triacetyloleandomymost susceptible. 3,8,9 cin. After 10 or 14 daily doses of cocaine, regenerative

The P450 (Cyp)* gene superfamily consists of a large changes with hepatocyte ballooning were observed, cogroup of different proteins, which catalyse the oxidative inciding with increases in CYP1A2, CYP2A4/5, and biotransformation of numerous xenobiotics and endoge-CYP3A. These results suggest the following: (1) cocaine nous compounds. It has been suggested that gene famienhances its own cytochrome P450-dependent metabolies 1, 2, and 3 are mainly responsible for the hepatic lism; (2) increased production of norcocaine in microxenobiotic metabolism. 14,15 Numerous experiments have somes is catalyzed mainly by CYP3A enzyme(s), whereas shown that microsomal oxidative enzymes are of importance in cocaine-induced hepatotoxicity. 7,16,17 However, Abbreviations: COH, coumarin 7-hydroxylase; PROD, 7-pentoxyresorufin there are contradictory reports about the individual CYP O-dealkylase; CNDM, cocaine N-demethylase; Cyp, cytochrome P450; TAO, forms mediating N-oxidative metabolism of cocaine. In triacetyloleandomycin. the rat liver, phenobarbital-inducible CYP2B1 catalyses From the