Sheweita Salah A
Department of Bioscience and Technology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
Toxicology. 2003 Sep 30;191(2-3):133-42. doi: 10.1016/s0300-483x(03)00252-x.
Drug-metabolizing enzymes play a great role in the bioactivation and also detoxification of zenobiotics and carcinogens such as N-nitrosamines and polycyclic aromatic hydrocarbons (PAHs). Therefore, the present study was undertaken to investigate the effect of narcotic drugs such as cannabis (hashish) and diacetylmorphine (heroin) on the activity of N-nitrosodimethylamine N-demethylase I [NDMA-dI], arylhydrocarbon [benzo(a)pyerne] hydroxylase [AHH], cytochrome P450 (CYP), cytochrome b(5), NADPH-cytochrome c reductase, glutathione-S-transferase, and levels of glutathione and thiobarbituric acid-reactive substances (TBARS). In addition, the present study showed the influence of hashish and heroin after single (24 h) and repeated-dose treatments (4 consecutive days) on the expression of cytochrome P450 2E1 (CYP 2E1) and cytochrome P450 2C6 (CYP 2C6). The expression of CYP 2E1 was slightly induced after single-dose and markedly induced after repeated dose-treatments of mice with hashish (10 mg kg(-1) body weight). Contrarily, heroin markedly induced the expression of CYP 2C6 after single-dose and potentially reduced this expression after repeated-dose treatments. It is believed that N-nitrosamines are activated principally by CYP 2E1 and in support of this, the activity of NDMA-dI was found to be increased after single- and repeated-dose treatments of mice with hashish by 23 and 41%, respectively. In addition, single- and repeated-dose treatments of mice with hashish increased: (1) the total hepatic content of CYP by 112 and 206%, respectively; (2) AHH activity by 110 and 165%, respectively; (3) NADPH-cytochrome c reductase activity by 21 and 98%, respectively; (4) and glutathione level by 81 and 173%, respectively. Also, single-dose treatments of mice with heroin increased the total hepatic content of CYP, AHH, NADPH-cytochrome c reductase, and glutathione level by 126, 72, 39, 205%, respectively. However, repeated dose-treatments of mice with heroin did not change such activities except cytochrome c reductase activity increased by 20%. Interestingly, the level of free radicals, TBARS, was potentially decreased after single or repeated-dose treatments with either hashish or heroin. It is clear from this study that the effects of hashish are different from those of heroin on the above mentioned enzymes particularly after repeated dose treatments. It is concluded that hashish induced the expression of CYP 2E1 and other carcinogen-metabolizing enzymes activities, and this induction could potentiate the deleterious effects of N-nitrosamines and aromatic hydrocarbons, e.g. benzo(a)pyrene, upon the liver and probably other organs. Such alterations may also change the therapeutic actions of other drugs, which are primarily metabolized by the P450 system, when administered to peoples using hashish or heroin.
药物代谢酶在异生物素和致癌物（如N-亚硝胺和多环芳烃（PAHs））的生物活化及解毒过程中发挥着重要作用。因此，本研究旨在探讨大麻（哈希什）和二乙酰吗啡（海洛因）等麻醉药物对N-亚硝基二甲胺N-脱甲基酶I [NDMA-dI]、芳烃[苯并(a)芘]羟化酶[AHH]、细胞色素P450（CYP）、细胞色素b5、NADPH-细胞色素c还原酶、谷胱甘肽-S-转移酶活性以及谷胱甘肽和硫代巴比妥酸反应性物质（TBARS）水平的影响。此外，本研究还显示了单次（24小时）和重复给药治疗（连续4天）后哈希什和海洛因对细胞色素P450 2E1（CYP 2E1）和细胞色素P450 2C6（CYP 2C6）表达的影响。用哈希什（10毫克/千克体重）对小鼠进行单次给药后，CYP 2E1的表达略有诱导，重复给药后则明显诱导。相反，海洛因单次给药后显著诱导CYP 2C6的表达，重复给药后则可能降低该表达。据信，N-亚硝胺主要由CYP 2E1激活，支持这一观点的是，用哈希什对小鼠进行单次和重复给药后，NDMA-dI的活性分别增加了23%和41%。此外，用哈希什对小鼠进行单次和重复给药后增加了：（1）肝脏中CYP的总含量，分别增加了112%和206%；（2）AHH活性，分别增加了110%和165%；（3）NADPH-细胞色素c还原酶活性，分别增加了21%和98%；（4）谷胱甘肽水平，分别增加了81%和173%。同样，用海洛因对小鼠进行单次给药后，肝脏中CYP、AHH、NADPH-细胞色素c还原酶和谷胱甘肽水平分别增加了126%、72%、39%、205%。然而，用海洛因对小鼠进行重复给药后，除细胞色素c还原酶活性增加了20%外，其他活性没有变化。有趣的是，用哈希什或海洛因进行单次或重复给药后，自由基水平TBARS可能会降低。从这项研究可以清楚地看出，哈希什和海洛因对上述酶的影响不同，尤其是在重复给药后。得出的结论是，哈希什诱导了CYP 2E1的表达以及其他致癌物代谢酶的活性，这种诱导可能会增强N-亚硝胺和芳烃（如苯并(a)芘）对肝脏以及可能对其他器官的有害影响。当给使用哈希什或海洛因的人施用主要由P450系统代谢的其他药物时，这种改变也可能会改变这些药物的治疗作用。
