Although CYP2C8, CYP2C9, and CYP2C19 play an important role in drug biotransformation, factors influencing the expression and activity of these CYP2C P450s in human liver remain largely undefined. We used primary cultures of human hepatocytes from 15 subjects to assess the inducibility of CYP2C enzyme expression by prototypical inducer agents, including rifampicin, dexamethasone, and phenobarbital. After culture for 72 h in serum-free medium on collagen, Western blotting revealed that CYP2C9 was the only CYP2C enzyme expressed at appreciable levels in untreated hepatocytes. Subsequent treatment with 25 M rifampicin for 48 h elicited marked increases in CYP2C8 (700 Ϯ 761%), CYP2C19 (854%), and CYP2C9 (209 Ϯ 176%) protein content versus a 550 Ϯ 170% enhancement of CYP3A4 enzyme levels. Parallel increases in CYP2C mRNAs, measured by Northern blotting and/or RNase protection, were found in rifampicintreated hepatocytes, with CYP2C8, CYP2C9, and CYP2C19 transcripts exhibiting increases of 688 Ϯ 635, 207 Ϯ 49, and 230 Ϯ 60%, respectively, versus an 8.8-fold enhancement of CYP3A4 mRNA levels. Dexamethasone (10 M) treatment enhanced CYP2C8 mRNA (360 Ϯ 100%) and protein (274%) content, although this steroid had less effect on CYP2C9 and CYP2C19 transcripts (23 Ϯ 21% and 21 Ϯ 36%, respectively) and enzyme levels (55 and 143%, respectively). Phenobarbital (100 M) was a powerful inducer of CYP2C9 (850%) and CYP2C19 (735%) mRNA content, and also increased CYP2C8 (610%) and CYP3A4 (205%) transcripts. Our results show that CYP2C enzyme expression in human hepatocytes is highly inducible by rifampicin, dexamethasone, and phenobarbital. Because these xenobiotics are ligands and/or activators of the pregnane X receptor and/or constitutive androstane receptor, such orphan nuclear receptors and their response elements may partake in regulating CYP2C gene expression in humans.
α‐Glucosidases are among the most important carbohydrate‐splitting enzymes. They catalyze the hydrolysis of α‐glucosidic linkages. Their substrates are—depending on their specificity—oligo‐ and polysaccharides. Microbial inhibitors of α‐amylases and other mammalian intestinal carbohydrate‐splitting enzymes studied during the last few years have aroused medical interest in the treatment of metabolic diseases such as diabetes. Moreover, they extend the spectrum of microbial secondary metabolites which comprises an enormous variety of structures. They also contribute considerably to a better understanding of the mechanism of action of α‐glucosidases. These inhibitors belong to different classes of substances. Those studied most thoroughly are microbial α‐glucosidase inhibitors which are members of a homologous series of pseudooligosaccharides of the general formula (4). They all have a core in common which is essential for their inhibitory action, a pseudodisaccharide residue consisting of an unsaturated cyclitol unit, and a 4‐amino‐4,6‐dideoxy‐ glucose unit. The—in many respects—most interesting representative of this homologous series is acarbose (5), a pseudotetrasaccharide exhibiting a very pronounced inhibitory effect on intestinal α‐glucosidases such as sucrase, maltase and glucoamylase. The present paper will review this new field of microbial α‐glucosidase inhibitors which has been studied with particular intensity during the past ten years.
The acetoacetate decarboxylase-like superfamily (ADCSF) is a group of ~4000 enzymes that, until recently, was thought to be homogeneous in terms of the reaction catalyzed. Bioinformatic analysis shows that the ADCSF consists of up to seven families that differ primarily in their active site architectures. The soil-dwelling bacterium Streptomyces bingchenggensis BCW-1 produces an ADCSF enzyme of unknown function that shares a low level of sequence identity (~20%) with known acetoacetate decarboxylases (ADCs). This enzyme, Sbi00515, belongs to the MppR-like family of the ADCSF because of its similarity to the mannopeptimycin biosynthetic protein MppR from Streptomyces hygroscopicus. Herein, we present steady state kinetic data that show Sbi00515 does not catalyze the decarboxylation of any α- or β-keto acid tested. Rather, we show that Sbi00515 catalyzes the condensation of pyruvate with a number of aldehydes, followed by dehydration of the presumed aldol intermediate. Thus, Sbi00515 is a pyruvate aldolase-dehydratase and not an acetoacetate decarboxylase. We have also determined the X-ray crystal structures of Sbi00515 in complexes with formate and pyruvate. The structures show that the overall fold of Sbi00515 is nearly identical to those of both ADC and MppR. The pyruvate complex is trapped as the Schiff base, providing evidence that the Schiff base chemistry that drives the acetoacetate decarboxylases has been co-opted to perform a new function, and that this core chemistry may be conserved across the superfamily. The structures also suggest possible catalytic roles for several active site residues.
Die Struktur des Pseudotetrasaccharids Acarbose (Ia), dessen Derivate (Ib) und (Ic) nach bekannter Methodik dargestellt werden, wird über chemische Abbaureaktionen aufgeklärt.
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