Ratanasavanh D, Berthou F, Dreano Y, Mondine P, Guillouzo A, Riche C
INSERM U49, Hospital Pontchaillou, Rennes, France.
Biochem Pharmacol. 1990 Jan 1;39(1):85-94. doi: 10.1016/0006-2952(90)90651-z.
Biotransformation of caffeine and theophylline and the effect of two well-known inducers of P-450 isozymes, namely phenobarbital (PB) and methylcholanthrene (3-MC) were studied in cultured hepatocytes from six human adult donors. Hepatocytes co-cultured with rat liver epithelial cells maintained a higher metabolic capacity than pure cultures. PB treatment of cultured hepatocytes for 3 days slightly increased the rate of caffeine metabolism 1.4 +/- 0.5-fold (N = 6) vs controls, and theophylline metabolism 1.2 +/- 0.4-fold (N = 6), whereas 3-MC treatment increased metabolism markedly 5.8 +/- 2.3- and 3.3 +/- 1.1-fold (N = 6) vs controls for caffeine and theophylline, respectively. Paraxanthine and theophylline formations from caffeine were the most induced by 3-MC. Their increase was significantly correlated (rs = 0.89, P less than 0.007) but not with TB formation, suggesting that at least two isozymes of the P-450IA family are involved in the first demethylations of caffeine. In addition, the N-1 demethylation of theophylline (mean increase of 554% vs controls) was not correlated with the N-1 demethylation of caffeine (mean to increase 247% vs controls) for the same donor after 3-MC treatment, suggesting that these two demethylations are mediated by a different P-450.
在来自六名成年人类供体的培养肝细胞中，研究了咖啡因和茶碱的生物转化以及两种著名的P-450同工酶诱导剂，即苯巴比妥（PB）和甲基胆蒽（3-MC）的作用。与大鼠肝上皮细胞共培养的肝细胞比纯培养物保持更高的代谢能力。用PB处理培养的肝细胞3天，咖啡因代谢率略有增加，相对于对照组为1.4±0.5倍（N = 6），茶碱代谢率为1.2±0.4倍（N = 6），而用3-MC处理则使咖啡因和茶碱的代谢相对于对照组分别显著增加5.8±2.3倍和3.3±1.1倍（N = 6）。3-MC对咖啡因生成副黄嘌呤和茶碱的诱导作用最强。它们的增加具有显著相关性（rs = 0.89，P < 0.007），但与TB生成无关，这表明P-450IA家族的至少两种同工酶参与了咖啡因的首次去甲基化。此外，在3-MC处理后，同一供体的茶碱N-1去甲基化（相对于对照组平均增加554%）与咖啡因的N-1去甲基化（相对于对照组平均增加247%）不相关，这表明这两种去甲基化是由不同的P-450介导的。
