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首页> 外文期刊>Biochemical Pharmacology >Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2.
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Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2.

机译：人和鼠CYP1A2在咖啡因和对黄嘌呤代谢上的差异。

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For the characterisation of murine models of CYP1A2 mediated metabolism in humans we compared the metabolism of caffeine and paraxanthine in human liver microsomes (LM) (two samples) and in LM from CYP1A2-null and wild-type mice. Inhibition experiments were carried out with the quinolones norfloxacin and pefloxacin and the substrate, caffeine. Additionally, in vivo pharmacokinetics of paraxanthine was determined in CYP1A2-null and wild-type mice. All LM produced the primary metabolites of caffeine and paraxanthine. In human LM, the main metabolite of caffeine was paraxanthine (K(M) 0.4 and 0.5 mmol L(-1)). In wild-type and CYP1A2-null mice LM, the main caffeine metabolite was 1,3,7-trimethylurate, but formation was not saturable. Apparent K(M) for paraxanthine formation from caffeine in wild-type and CYP1A2-null murine LM were 0.2 and 4.9 mmol L(-1), respectively. The main metabolite of paraxanthine was 1-methylxanthine in human (K(M) 0.13 and 0.2 mmol L(-1)) and in wild-type mice LM (K(M) 0.53 mmol L(-1)). In CYP1A2-null murine LM, the main paraxanthine metabolite was 7-methylxanthine. The quinolones competitively inhibited caffeine metabolism in human but not in wild-type or CYP1A2-null murine LM. No obvious differences were seen for blood pharmacokinetics and urinary metabolite excretion of paraxanthine between CYP1A2-null and wild-type mice. Thus, for paraxanthine, norfloxacin and pefloxacin interaction with CYP1A2 there were clear differences between mice and man. Our results suggest that an interspecies comparison is required for the metabolism of individual xenobiotics interacting with CYP1A2 prior to the use of mice models to predict its toxicity and/or pharmacological activity in man.
机译：为表征CYP1A2介导的人类代谢的小鼠模型，我们比较了人肝微粒体（LM）（两个样品）和CYP1A2无效小鼠和野生型小鼠的LM中咖啡因和对黄嘌呤的代谢。用喹诺酮诺氟沙星和培氟沙星以及底物咖啡因进行抑制实验。此外，在CYP1A2无效和野生型小鼠中确定了对黄嘌呤的体内药代动力学。所有LM均产生咖啡因和对黄嘌呤的主要代谢产物。在人类LM中，咖啡因的主要代谢产物是对黄嘌呤（K（M）0.4和0.5 mmol L（-1））。在野生型和CYP1A2无效的LM小鼠中，咖啡因的主要代谢产物是1,3,7-三甲基尿酸酯，但形成并不饱和。从咖啡因在野生型和CYP1A2空鼠LM中咖啡因形成黄嘌呤的表观K（M）分别为0.2和4.9 mmol L（-1）。对位黄嘌呤的主要代谢产物是人（K（M）0.13和0.2 mmol L（-1））和野生型LM（K（M）0.53 mmol L（-1））中的1-甲基黄嘌呤。在CYP1A2无效的鼠LM中，主要的副黄嘌呤代谢物是7-甲基黄嘌呤。喹诺酮类药物竞争性抑制人体内的咖啡因代谢，但对野生型或CYP1A2无效鼠类LM却没有抑制作用。在CYP1A2无效和野生型小鼠之间，对黄嘌呤的血液药代动力学和尿代谢产物排泄没有明显差异。因此，对于对黄嘌呤，诺氟沙星和培氟沙星与CYP1A2的相互作用，小鼠和人之间存在明显差异。我们的结果表明，在使用小鼠模型预测其在人体内的毒性和/或药理活性之前，与CYP1A2相互作用的单个异生物的代谢需要进行种间比较。

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