Cytochrome P450 (Cyp) enzymes from the first four families (Cyp1-4) play a major role in metabolizing xenobiotics, affecting drug pharmacokinetics and chemical-induced toxicity. Due to cloning of the mouse genome, many novel Cyp isoforms have been identified, but their tissue distribution of expression is unknown. This study compared the tissue distribution of all 78 Cyps from the Cyp1-4 families in C57BL/6 mice providing not only an indication of which tissues novel Cyps may have their greatest importance but also a cohesive comparison of the tissue distribution of all Cyp1-4 isoforms. Transcripts of the 78 Cyps were quantified by multiplex suspension arrays and quantitative real-time PCR in 14 tissues. Hierarchical clustering indicated that in male mice, 52% of the Cyp species were expressed highest in liver, 10% in kidney, 10% in duodenum/jejunum, 10% in testes, 5% in lung, and < 4% in colon, brain, heart, and stomach. Female mice had a similar pattern of Cyp messenger RNA expression; however, compared with males, females had 7% more Cyps that were liver predominant, 2% more Cyps that were stomach predominant, but 1% less Cyps that were kidney and lung predominant. Differences in gender expression were observed in 29 of the Cyps, with 24 being higher in females than males. Additionally, the data suggest a correlation between the spatial arrangement of genes within a gene cluster and their organ-predominant expression, indicating a common regulatory mechanism may be present within these clusters. In conclusion, this study provides novel data on the tissue distribution and gender-divergent expression of 78 functional mouse Cyp isoforms.

Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin+imipenem and cephalothin+neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vacomycin+imipenem but stimulated by cephalothin+neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism.

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Nutritional intake is a fundamental determinant of health. Many studies have correlated excess caloric intake, as well as a high ratio of n-6:n-3 fatty acids, with detrimental health outcomes, such as the metabolic syndrome. In contrast, low-calorie diets have beneficial health effects. Despite these associations, our understanding of the causal relationship between diet and health remains largely elusive. The present study examined the molecular changes elicited by nine diets with varying fat, sugar, cholesterol, omega-3 fatty acids, omega-6 fatty acids, and calories in C57BL/6 male mice. Microarray analyses were conducted on liver samples from three mice per diet and detected 20,449 genes of which 3,734 were responsive to changes in dietary components. Principal component analysis showed that diet restriction correlated the least with the other diets and also affected more genes than any other diet. Interestingly, Gene Set Enrichment Analysis (GSEA) identified gene sets involved in glutathione metabolism, immune response, fatty acid metabolism, cholesterol metabolism, ABC transporters, and oxidative phosphorylation as being highly responsive to changes in diet composition. On the gene level, this study reveals novel findings such as the induction of the drug efflux pump Abcb1a (p-glycoprotein) by diet restriction and an atherogenic diet, as well as the suppression of the rate limiting step of bile acid synthesis, Cyp7a1, by a high fructose diet. This study provides considerable insight into the molecular changes incurred by a variety of diets and furthers our understanding of the causal relationships between diet and health.

During development, the maturation of liver transporters is essential for chemical elimination in newborns and children. One cannot compare the real abundance of transcripts by conventional messenger RNA (mRNA) profiling methods; in comparison, RNA-Seq provides a "true quantification" of transcript counts and an unbiased detection of novel transcripts. The purpose of this study was to compare the mRNA abundance of liver transporters and seek their novel transcripts during liver development. Livers from male C57BL/6J mice were collected at 12 ages from prenatal to adulthood. The transcriptome was determined by RNA-Seq, with transcript abundance estimated by Cufflinks. Among 498 known transporters, the ontogeny of 62 known critical xenobiotic transporters was examined in detail. The cumulative mRNAs of the uptake transporters increased more than the efflux transporters in livers after birth. A heatmap revealed three ontogenic patterns of these transporters, namely perinatal (reaching maximal expression before birth), adolescent (about 20 days), and adult enriched (about 60 days of age). Before birth, equilibrative nucleoside transporter 1 was the transporter with highest expression in liver (29%), followed by breast cancer resistance protein (Bcrp) (26%). Within 1 day after birth, the mRNAs of these two transporters decreased markedly, and Ntcp became the transporter with highest expression (52%). In adult liver, the transporters with highest expression were organic cation transporter 1 and Ntcp (23% and 22%, respectively). Three isoforms of Bcrp with alternate leading exons were identified (E1a, E1b, and E1c), with E1b being the major isoform. In conclusion, this study reveals the mRNA abundance of transporters in liver and demonstrates that the expression of liver transporters is both age and isoform specific.

ABSTRACT:The ontogeny of the first four families of cytochromes P450 (P450s) (i.e., Cyp1-Cyp4) can affect the biotransformation of drugs and dietary chemicals in liver, resulting in unique pharmacological reactions in children. Because genome-scale investigations have identified many novel P450 isoforms, it is critical to perform a systematic characterization of these P450s during liver development. In this study, livers were collected from C57BL/6 mice 2 days before birth and at various postnatal ages (0-45 days of age). The mRNA levels for 75 P450 isoforms (Cyp1-Cyp4) were quantified with branched DNA assays and reverse transcription-polymerase chain reaction assays. More than half of the mouse P450s are conserved in humans, but there are more isoforms in mice. The P450 mRNA levels increased after birth in mouse liver, forming four distinct ontogenic patterns. The majority of P450s form a total of eight genomic clusters, namely, Cyp1a1 and Cyp1a2 genes on chromosome 9 (cluster 1), Cyp2a, Cyp2b, Cyp2f, Cyp2g, and Cyp2t genes on chromosome 7 (cluster 2), Cyp2c genes on chromosome 19 (cluster 3), Cyp2d genes on chromosome 15 (cluster 4), Cyp2j genes on chromosome 4 (cluster 5), Cyp3a genes on chromosome 5 (cluster 6), Cyp4a, Cyp4b, and Cyp4x genes on chromosome 4 (cluster 7), and Cyp4f genes on chromosome 17 (cluster 8). Some P450 isoforms within the same genomic cluster showed similar ontogenic patterns. In conclusion, the present study revealed four patterns of ontogeny for P450s in liver and showed that many P450s within a genomic cluster exhibited similar ontogenic patterns, which suggests that some P450s within a cluster are likely regulated by a common pathway during liver development.

The xenobiotic-sensing transcription factors (xeno-sensors) AhR, CAR, and PXR upregulate the expression of many drug-processing genes (DPGs) in liver. Previous studies have unveiled profound changes in the basal expression of DPGs during development; however, knowledge on the ontogeny of the inducibility of DPGs in response to pharmacological activation of xeno-sensors is still limited. The goal of this study was to investigate the age-specific regulation of DPGs by prototypical xeno-sensor ligands: 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for AhR; 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) for CAR; and pregnane-16a-carbonitrile (PCN) for PXR during mouse liver development. The basal mRNAs of most DPGs were low during neonatal age, but gradually increased to adult levels, whereas some DPGs (Cyp1a2, Cyp2b10, Cyp3a11, Gstm2, Gstm3, Papss2, and Oatp1a4) exhibited an adolescent-predominant expression pattern. The inducibility of DPGs was age-specific: 1) during neonatal age, the highest fold increase in the mRNA expression was

Griseofulvin was the treatment of choice for tinea capitis in the 1950s; however, newer treatments have emerged, ketoconazole, terbinafine, itraconazole, and fluconazole. 1-3 The efficacy and safety of many monotherapies used for tinea capitis have not been simultaneously compared in a randomized controlled trial (RCT) study design; information on relative efficacy and safety is relevant to medical practice and health policy. We conducted a systematic review and network meta-analyses (NMAs) to determine the relative efficacy