1.
Gut microbiota as an "invisible organ" that modulates the function of drugs.
Li, X, Liu, L, Cao, Z, Li, W, Li, H, Lu, C, Yang, X, Liu, Y
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:109653
Abstract
Gut microbiota plays an important role in the gut and have become a hotspot of recent research interests. Commensal microbiota in gut exert a variety of effects on the host, from shaping the structure and function of the gut and the immune system to the modulation of nutrient status of the host and the treatment outcomes of some drugs. Gut microbiota and its enzyme product and subsequent products, such as short-chain fatty acid and bile acid, play important roles in the biotransformation of drugs via directly or indirectly affecting drug absorption, toxicity, metabolism and bioavailability. Drugs, especially antibiotics, also affect the homeostasis of probiotics and the integrity and function of the intestinal mucosa. These interplaying processes produce a variety of important metabolites of the host and drugs and affect the balance of microbiota and the mucosal barrier then modulate the function of drugs. Gut microbiota imbalance is associated with a broad range of disease mechanisms, and this association denotes a new drug-therapeutic avenue. The present review summarizes how gut microbiota acts as an "invisible organ" to directly or indirectly modulate the function of drugs, on the aspects of probiotic homeostasis, drugs and host nutritional metabolism, AJC, mucus layer and microfold cells.
2.
Detection of Beta-Glucan Contamination in Nanotechnology-Based Formulations.
Neun, BW, Cedrone, E, Potter, TM, Crist, RM, Dobrovolskaia, MA
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety profiles. IIMIs are a large family of molecules with diverse compositions and structures that contribute to the immune-mediated adverse effects (IMAE) of drug products. Pyrogenicity (the ability to induce fever) and activation of innate immune responses underlying both acute toxicities (e.g., anaphylactoid reactions or pseudoallergy, cytokine storm) and long-term effects (e.g., immunogenicity) are among the IMAE commonly related to IIMI contamination. Endotoxins of gram-negative bacteria are the best-studied IIMIs in that both methodologies for and pitfalls in their detection and quantification are well established. Additionally, regulatory guidance documents and research papers from laboratories worldwide are available on endotoxins. However, less information is currently known about other IIMIs. Herein, we focus on one such IIMI, namely, beta-glucans, and review literature and discuss the experience of the Nanotechnology Characterization Lab (NCL) with the detection of beta-glucans in nanotechnology-based drug products.
3.
Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism.
Annalora, AJ, Marcus, CB, Iversen, PL
Drug metabolism and disposition: the biological fate of chemicals. 2017;(4):375-389
Abstract
The human genome encodes 57 cytochrome P450 genes, whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics, and unknown numbers of endogenous compounds, including steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several National Institutes of Health databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human P450 transcriptome. This review describes a remarkable diversification of the 57 human P450 genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's P450 proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, 3A, 4F, 19A, and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of P450 transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, trans-splicing between gene transcripts, single-nucleotide polymorphisms, and epigenetic regulation of alternate splicing. Homeostatic regulation of variant P450 expression is influenced also by nuclear receptor signaling, suppression of nonsense-mediated decay or premature termination codons, mitochondrial dysfunction, or host infection. This review focuses on emergent aspects of the adaptive gene-splicing process, which when viewed through the lens of P450-nuclear receptor gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.