University of Cagliari, Department of Pathology, Cagliari, Italy.
Catholic University, Faculty of Medicine, Institute of Biochemistry and Clinical Biochemistry, Rome, Italy.
Int J Immunopathol Pharmacol. 2014 Jan-Mar;27(1):5-13. doi: 10.1177/039463201402700102.
The cytochrome P450 superfamily (CYP450) in humans is formed by 57 functional monooxygenases critical for the metabolism of numerous endogenous and exogenous compounds. The superfamily is organized into 18 families and 44 subfamilies. CYP nomenclature is based on the identity of amino acids. The most important functions of the CYP450 are related to metabolism of endogenous compounds, detoxification of exogenous xenobiotics and decomposition of the vast majority of currently used drugs. The expression of CYP450 enzymes in the human body is characterized by a marked substrate and tissue specificity, the most important being localized in the liver, but also present in kidney, lung, brain, breast, prostate and in the small intestine. The human cytochrome P450 3A gene family (CYP3A) accounts for the largest portion of CYP450 proteins in human liver and includes 4 genes: CYP3A4, CYP3A5, CYP3A7, CYP3A43. Multiple and complex genetic variations, marked interindividual, interethnic and gender variability have been reported regarding CYP3A isoform expression and activity. Multiple factors may affect CYP3A expression and activity, such as inducers like rifampicin, phenobarbital, 3-methylcholantrene, beta-naphtoflavone, and dexamethasone. The maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of postnatal life, surely exerts profound effects on drug disposition, probably being the predominant factor accounting for age-associated changes in drug clearance. In fact, drug dosage in the perinatal period represents a continuous challenge for neonatologists. The purpose of this article is to provide a brief review of the pharmacokinetic differences between neonates and adults, showing the peculiarities of liver CYP450-related drug metabolism in the perinatal period and at birth, and to report the toxic mechanisms of liver injury in neonates, due to the most frequently utilized drugs in NICU centers.
人体内的细胞色素 P450 超家族（CYP450）由 57 种功能单加氧酶组成，这些酶对于许多内源性和外源性化合物的代谢至关重要。该超家族分为 18 个家族和 44 个亚家族。CYP 命名法基于氨基酸的同一性。CYP450 的最重要功能与内源性化合物的代谢、外源性异生物质的解毒以及目前使用的绝大多数药物的分解有关。人体 CYP450 酶的表达具有明显的底物和组织特异性，最重要的是定位于肝脏，但也存在于肾脏、肺、脑、乳房、前列腺和小肠中。人类细胞色素 P450 3A 基因家族（CYP3A）占人类肝脏 CYP450 蛋白的最大部分，包括 4 个基因：CYP3A4、CYP3A5、CYP3A7、CYP3A43。关于 CYP3A 同工型的表达和活性，已经报道了多种复杂的遗传变异，个体间、种族间和性别间的差异显著。多种因素可能影响 CYP3A 的表达和活性，如诱导剂如利福平、苯巴比妥、3-甲基胆蒽、β-萘黄酮和地塞米松。器官系统的成熟，伴随着胎儿期和出生后头几个月药物代谢酶的个体发生，肯定会对药物处置产生深远影响，可能是导致与年龄相关的药物清除率变化的主要因素。事实上，围产期的药物剂量对新生儿科医生来说是一个持续的挑战。本文旨在简要综述新生儿与成人之间的药代动力学差异，展示围产期和出生时肝 CYP450 相关药物代谢的特点，并报告新生儿肝损伤的毒性机制，这是新生儿重症监护病房（NICU）中心最常使用的药物。
