Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants
Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants
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DOI：
10.1203/01.pdr.0000245909.74166.00
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发表时间：
2006-12-01
影响因子：
3.6
通讯作者：
Kearns, Gregory L.
中科院分区：
文献类型：
--
作者：
Blake, Michael J.;Abdel-Rahman, Susan M.;Kearns, Gregory L.
口服咖啡因和美沙芬（DM）被用作药理学探针，以确定婴儿饮食对生命最初6个月内细胞色素P-450（CYP）酶活性的影响。从血清中测定咖啡因消除速率常数（k（e）），并通过高效液相色谱法（HPLC）测定尿液中咖啡因、DM及其各自代谢物的浓度。咖啡因k（e）在2周时较低，并与年龄呈显著的正线性相关（p < 0.001）;配方奶喂养的婴儿比母乳喂养的婴儿增加更快（p < 0.001）。这与尿中1，7-二甲基黄嘌呤（17倍）和I-甲基黄嘌呤（1倍）的显著增加同时发生（p < 0.001），表明配方奶粉喂养的婴儿更快获得CYP 1A 2活性。尿中（17 X +1 X）/咖啡因摩尔比和年龄与咖啡因k（e）呈显著正相关（r（2）= 0.65; p < 0.001），与喂养方式无关。以3-羟基吗啡喃/右啡烷的摩尔比评估的CYP 3A 4活性显示出类似的随出生后年龄的显著增加（p < 0.001），配方奶粉喂养的婴儿也比母乳喂养的婴儿更大。配方奶喂养似乎通过分别增加CYP 1A 2和CYP 3A 4的活性来加速咖啡因和DM代谢的成熟。膳食中对外源性活性的改变可能会调节药物的生物转化，从而改变从很小的年龄开始对外源性物质的全身暴露。
Orally administered caffeine and dextromethorphan (DM) were used as pharmacologic probes to determine the effect of infant diet on acquisition of cytochrome P-450 (CYP) enzyme activity during the first 6 mo of life. The caffeine elimination rate constant (k(e)) was determined from serum, and concentrations of caffeine, DM, and their respective metabolites were measured in urine by high-performance liquid chromatography (HPLC). Caffeine k(e) was low at 2 wk and displayed a significant positive linear correlation with age (p < 0.001); increasing faster in formula-fed than in breast-fed infants (p < 0.001). This occurred concomitantly with a significant increase in urinary 1,7-dimethylxanthine (17X) and I-methylxanthine (1X) (p < 0.001), suggesting faster acquisition of CYP1A2 activity in formula-fed infants. The urinary molar ratio of (17X + 1X)/caffeine and age strongly predicted caffeine k(e) (r(2) = 0.65; p < 0.001) irrespective of feeding type. CYP3A4 activity, assessed as the molar ratio of 3-hydroxymorphinan/dextrorphan showed a similar marked increase with postnatal age (p < 0.001) that was also greater in formula-fed than in breast-fed infants. Formula feeding appears to accelerate maturation of caffeine and DM metabolism by increasing the activity of CYP1A2 and CYP3A4, respectively. Dietary modification of CYP activity may modulate drug biotransformation and thus alter systemic exposure to xenobiotics from a very early age.