The cytochrome P450 enzyme CYP3A4 is highly expressed in the intestinal mucosa, where it plays a critical role in the first-pass metabolism of orally administered drugs and thereby influences systemic bioavailability ...The cytochrome P450 enzyme CYP3A4 is highly expressed in the intestinal mucosa, where it plays a critical role in the first-pass metabolism of orally administered drugs and thereby influences systemic bioavailability and drug re- sponse. For example, approximately 45% of an oral dose of the sedative/hypnotic agent midazolam can be inactiva- ted by CYP3A4-dependent 1 -and 4-hydroxylation, necessitating a higher oral dose than an intravenous dose to a- chieve adequate pharmacological response. Unfortunately, there is substantial inter- individual variability in the level of CYP3A4 expressed in the small intestine and this contributes to unpredictability in patient response to this drug and the many other high first-pass CYP3A4 substrates. Over the last 20 years, we have sought to identify and characterize genetic and environmental sources of variable intestinal CYP3A4 expression, with the goal of using that information to guide individual drug dosing decisions in clinical practice. Interestingly, unlike some of the other members of the drug-metabolizing human P450 family, there is only limited variation in the CYP3A4 gene and cod- ing or other highly deleterious variants are rare, despite the fact that CYP3A4 activity in vivo is thought to be highly heritable. More common variation, such as the CYP3A4 ＊ 1Gand CYP3A4 ＊ 22alleles, may influence gene expres- sion, but effect sizes are relatively small. Thus, much of our attention today is focused on the regulation of CYP3A4. With colleagues at St Jude Children＇s Research Hospital, we showed that vitamin D is an important reg- ulator of intestinal CYP3 A4 via a vitamin D receptor - mediated process and that its effects may be exerted predomi- nantly in the duodenum and jejunum, where CYP3A4 expression is most prominent. We have postulated that variation in vitamin D levels and its regulation contribute to variation in intestinal CYP3A4 function. The metabo- lism of 25 - hydroxy vitamin D3 （25 OHD3 ） plays a central role in regulating the effects of the hormon展开更多
文摘The cytochrome P450 enzyme CYP3A4 is highly expressed in the intestinal mucosa, where it plays a critical role in the first-pass metabolism of orally administered drugs and thereby influences systemic bioavailability and drug re- sponse. For example, approximately 45% of an oral dose of the sedative/hypnotic agent midazolam can be inactiva- ted by CYP3A4-dependent 1 -and 4-hydroxylation, necessitating a higher oral dose than an intravenous dose to a- chieve adequate pharmacological response. Unfortunately, there is substantial inter- individual variability in the level of CYP3A4 expressed in the small intestine and this contributes to unpredictability in patient response to this drug and the many other high first-pass CYP3A4 substrates. Over the last 20 years, we have sought to identify and characterize genetic and environmental sources of variable intestinal CYP3A4 expression, with the goal of using that information to guide individual drug dosing decisions in clinical practice. Interestingly, unlike some of the other members of the drug-metabolizing human P450 family, there is only limited variation in the CYP3A4 gene and cod- ing or other highly deleterious variants are rare, despite the fact that CYP3A4 activity in vivo is thought to be highly heritable. More common variation, such as the CYP3A4 ＊ 1Gand CYP3A4 ＊ 22alleles, may influence gene expres- sion, but effect sizes are relatively small. Thus, much of our attention today is focused on the regulation of CYP3A4. With colleagues at St Jude Children＇s Research Hospital, we showed that vitamin D is an important reg- ulator of intestinal CYP3 A4 via a vitamin D receptor - mediated process and that its effects may be exerted predomi- nantly in the duodenum and jejunum, where CYP3A4 expression is most prominent. We have postulated that variation in vitamin D levels and its regulation contribute to variation in intestinal CYP3A4 function. The metabo- lism of 25 - hydroxy vitamin D3 （25 OHD3 ） plays a central role in regulating the effects of the hormon
