Nash R M, Stein L, Penno M B, Passananti G T, Vesell E S
Clin Pharmacol Ther. 1984 Oct;36(4):417-30. doi: 10.1038/clpt.1984.199.
Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six sets of dizygotic (DZ) twins. All were normal, nonsmoking, nonmedicated, and male. Among these 24 subjects, there were 300% interindividual variations in rate constants for formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as large within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations support this conclusion: Intraindividual variations were frequently as large as interindividual variations, and regardless of zygosity for twins living together, intratwin correlation coefficients were almost twice those of twins living apart. Quite different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions reveals that interindividual variations in APAP metabolism arise from certain unidentified environmental factors, whereas genetic factors cause the large interindividual variations that occur in antipyrine disposition.
我们的目标是在同卵双胞胎中比较和对比遗传因素和环境因素对乙酰氨基酚（APAP）和安替比林代谢中个体间巨大差异的相对贡献。选择这两种药物是因为它们通过不同的机制进行生物转化。给六对同卵（MZ）双胞胎和六对异卵（DZ）双胞胎口服单一剂量的APAP（10 mg/kg）。所有受试者均为正常、不吸烟、未用药的男性。在这24名受试者中，硫酸盐和葡萄糖醛酸结合物形成的速率常数以及APAP消除的总速率常数存在300%的个体间差异。同卵双胞胎中每项测量的双胞胎内差异与异卵双胞胎中的差异一样大，这表明个体间差异主要由环境因素而非遗传因素维持。另外两个观察结果支持这一结论：个体内差异常常与个体间差异一样大，并且无论共同生活的双胞胎的合子性如何，共同生活的双胞胎的双胞胎内相关系数几乎是分开生活的双胞胎的两倍。当这些双胞胎服用安替比林时，得到了截然不同的结果。口服单一剂量的安替比林（18 mg/kg）后，安替比林三种主要氧化代谢物形成的速率常数出现500%的个体间差异，这似乎主要受遗传控制。同样对于安替比林及其主要代谢物，个体内差异远小于个体间差异。与APAP的结果相反，无论合子性如何，分开生活的双胞胎和共同生活的双胞胎的安替比林双胞胎内相关系数相似。在明显一致的环境条件下，对同一组精心挑选的正常双胞胎中APAP和安替比林代谢的这种比较表明，APAP代谢中的个体间差异源于某些未明确的环境因素，而遗传因素导致了安替比林处置中出现的个体间巨大差异。
