CYP2C9, CYP3A and CYP2C19 metabolize Δ9-tetrahydrocannabinol to multiple metabolites but metabolism is affected by human liver fatty acid binding protein (FABP1).

Δ9-tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis. It is cleared predominantly via metabolism. Metabolism to 11-OH-THC by cytochrome P450 (CYP) 2C9 has been proposed as the main clearance pathway of THC, with the estimated fraction metabolized (fm) about 70%. The remaining clearance pathways are not well established, and it is unknown how THC is eliminated in individuals with reduced CYP2C9 activity. The goal of this study was to systematically identify the CYP enzymes contributing to THC clearance and characterize the metabolites formed. Further, this study aimed to characterize the impact of liver fatty acid binding protein (FABP1) on THC metabolism by human CYPs. THC was metabolized to at least four different metabolites including 11-OH-THC in human liver microsomes (HLMs) and with recombinant CYPs. 11-OH-THC was formed by recombinant CYP2C9 (Km,u = 0.77 nM, kcat = 12 min-1) and by recombinant CYP2C19 (Km,u = 2.2 nM, kcat = 14 min-1). The other three major metabolites were likely hydroxylations in the cyclohexenyl ring and were formed mainly by recombinant CYP3A4/5 (Km,u > 10 nM). HLM experiments confirmed the contributions of CYP2C9, CYP2C19 and CYP3A to THC metabolism. The presence of FABP1 and THC binding to FABP1 altered THC metabolism by recombinant CYPs and HLMs in an enzyme and metabolite specific manner. This suggests that FABP1 may interact with CYP enzymes and alter the fm by CYPs towards THC metabolism. In conclusion, this study is the first to systematically establish the metabolic profile of THC by human CYPs and characterize how FABP1 binding alters CYP mediated THC metabolism.

Gaussian curvature dilutes the nuclear lamina, favoring nuclear rupture, especially at high strain rate.

Nuclear rupture has long been associated with deficits or defects in lamins, with recent results also indicating a role for actomyosin stress, but key physical determinants of rupture remain unclear. Here, lamin-B filaments stably interact with the nuclear membrane at sites of low Gaussian curvature yet dilute at high curvature to favor rupture, whereas lamin-A depletion requires high strain-rates. Live-cell imaging of lamin-B1 gene-edited cancer cells is complemented by fixed-cell imaging of rupture in: iPS-derived progeria patients cells, cells within beating chick embryo hearts, and cancer cells with multi-site rupture after migration through small pores. Data fit a model of stiff filaments that detach from a curved surface.Rupture is modestly suppressed by inhibiting myosin-II and by hypotonic stress, which slow the strain-rates. Lamin-A dilution and rupture probability indeed increase above a threshold rate of nuclear pulling. Curvature-sensing mechanisms of proteins at plasma membranes, including Piezo1, might thus apply at nuclear membranes.Summary statement: High nuclear curvature drives lamina dilution and nuclear envelope rupture even when myosin stress is inhibited. Stiff filaments generally dilute from sites of high Gaussian curvature, providing mathematical fits of experiments.

Photosystem I Enhances the Efficiency of a Natural, Gel-Based Dye-Sensitized Solar Cell.

The photosystem I (PSI) protein complex is known to enhance bioelectrode performance for many liquid-based photoelectrochemical cells. A hydrogel as electrolyte media allows for simpler fabrication of more robust and practical solar cells in comparison to liquid-based devices. This paper reports a natural, gel-based dye-sensitized solar cell that integrates PSI to improve device efficiency. TiO2-coated FTO slides, dyed by blackberry anthocyanin, act as a photoanode, while a film of PSI deposited onto copper comprises the photocathode. Ascorbic acid (AscH) and 2,6-dichlorophenolindophenol (DCPIP) are the redox mediator couple inside an agarose hydrogel, enabling PSI to produce excess oxidized species near the cathode to improve device performance. A comparison of performance at low pH and neutral pH was performed to test the pH-dependent properties of the AscH/DCPIP couple. Devices at neutral pH performed better than those at lower pH. The PSI film enhanced photovoltage by 75 mV to a total photovoltage of 0.45 V per device and provided a mediator concentration-dependent photocurrent enhancement over non-PSI devices, reaching an instantaneous power conversion efficiency of 0.30% compared to 0.18% without PSI, a 1.67-fold increase. At steady state, power conversion efficiencies for devices with and without PSI were 0.042 and 0.028%, respectively.