Drug biotransformation and its therapeutic effect may be modified during ageing. Among different causative factors of ageing, the impairment of normal cellular functions by free radicals has been ...evoked as playing a critical role. The effect of age on the expression and activity of CYP2E1 and CYP3A was investigated in male Wistar rats of 3, 8, 11 and 18 months old. The total cytochrome P450 as well as the expression and the activity (midazolam oxidation) of CYP3A isoforms did not change until 18 months of age. Chlorzoxazone hydroxylation (CYP2E1 activity) increased from 3 to 8 months, remained constant between 8 and 11 months and then progressively decreased until 18 months. Interestingly, CYP2E1 microsomal protein followed the same enzyme activity profile from 3 to 8 months, but remained constant thereafter. The level of CYP2E1 mRNA did not change over the whole period. While the amount of proteins did not change after 8 months, their functionality may be affected by oxidative stress (increase in thiobarbituric acid reactive substances, decrease in reduced glutathione level). However, no changes in carbonyl protein content were observed. The decrease in CYP2E1 activity in rats after 11 months is most probably due to post-translational modifications of CYP2E1 proteins. Indeed, it may be correlated with an accumulation of oxidative damage. Since no change was observed in CYP3A activity or in their protein and mRNA content, it seems that such isoforms should be less affected by oxidative stress.
The effect of ageing on CYP3A2, a male specific isoform, was examined in adult (9 months) and senescent (24 months) male rats. A significant decrease (65%) of CYP3A2-related activity (midazolam ...oxidation) was observed in all senescent rats. Half of these rats still express CYP3A2 suggesting that decreased activities in these rats are due to post-translational modifications. The other senescent male rats did not express CYP3A2 anymore, indicating an impairment of transcription. These transcriptional modifications are due to the previously shown continuous secretion of GH in senescent male rats. GH also regulates HNF4alpha, a hepatocyte nuclear factor, essential for the basal transcriptional activation of the CYP3A2 gene. In senescent rats, a drastic reduction (76%) of HNF4alpha protein content and a decrease in DNA binding activity were observed. When these parameters were assessed in male and female rats of the same age (3 months), a higher HNF4alpha DNA binding activity and a higher HNF4alpha protein content (38%) were observed in female rats. Our results show that in male senescent rats (1) the decrease of HNF4alpha is not consistent with the continuous secretion of GH, and (2) the suppression of CYP3A2 expression is not dependent to the HNF4alpha binding activity.
Precision-cut liver slices (PCLS) offer a lot of advantages because all heterogeneity and cell-cell interactions within the original tissue matrix are maintained. This in vitro model was used to ...study the effect of ageing on certain aspects of drug metabolism and liver function in young (3 months), adult (9 months) and old (24 months) Wistar male rats. Protein synthesis, an important liver function, was not modified in young, adult and old rats, suggesting that ageing does not impair liver functionality but it affects some specific targets. Among them, a decrease in total P450 in liver microsomes and the loss of CYP3A23 inducibility in PCLS were clearly observed in old rats as compared to adult rats. Finally, the amount of total paracetamol conjugates was not modified between 9 and 24 months but in old rats, sulfoconjugation of paracetamol, its major route of elimination, was decreased.
On 17 January 2002, Nyiragongo volcano erupted along a 20 km‐long fracture network extending from the volcano to the city of Goma. The event was captured by InSAR data from the ERS‐2 and RADARSAT‐1 ...satellites. A combination of 3D numerical modeling and inversions is used to analyze these displacements. Using Akaike Information Criteria, we determine that a model with two subvertical dikes is the most likely explanation for the 2002 InSAR deformation signal. A first, shallow dike, 2 km high, is associated with the eruptive fissure, and a second, deeper dike, 6 km high and 40 km long, lies about 3 km below the city of Goma. As the deep dike extends laterally for 20 km beneath the gas‐rich Lake Kivu, the interaction of magma and dissolved gas should be considered as a significant hazard for future eruptions. A likely scenario for the eruption is that the magma supply to a deep reservoir started ten months before the eruption, as indicated by LP events and tremor. Stress analysis indicates that the deep dike could have triggered the injection of magma from the lake and shallow reservoir into the eruptive dike. The deep dike induced the opening of the southern part of this shallow dike, to which it transmitted magma though a narrow dike. This model is consistent with the geochemical analysis, the lava rheology and the pre‐ and post‐eruptive seismicity. We infer low overpressures (1–10 MPa) for the dikes. These values are consistent with lithostatic crustal stresses close to the dikes and low magma pressure. As a consequence, the dike direction is probably not controlled by stresses but rather by a reduced tensile strength, inherited from previous rift intrusions. The lithostatic stresses indicate that magmatic activity is intense enough to relax tensional stresses associated with the rift extension.
Key Points
Modeling of the January 2002 Nyiragongo eruption captured by InSAR
Hazard associated with a deep dike beneath Lake Kivu
Magmatic activity relaxes tensional stresses associated with the rift extension
A summit and upper flank eruption occurred at Nyamulagira volcano, Democratic Republic of Congo, from 2-27 January 2010. Eruptions at Nyamulagira during 1996-2010 occurred from eruptive fissures on ...the upper flanks or within the summit caldera and were distributed along the ~N155E rift zone, whereas the 2011-2012 eruption occurred ~12 km ENE of the summit. 3D numerical modeling of Interferometric Synthetic Aperture Radar (InSAR) geodetic measurements of the co-eruptive deformation in 2010 reveals that magma stored in a shallow (~3.5 km below the summit) reservoir intruded as two subvertical dikes beneath the summit and southeastern flank of the volcano. The northern dike is connected to an ~N45E-trending intra-caldera eruptive fissure, extending to an ~2.5 km maximum depth. The southern dike is connected to an ~N175E-trending flank fissure extending to the depth of the inferred reservoir at ~3.5 km. The inferred reservoir location is coincident with the reservoir that was active during previous eruptions in 1938-1940 and 2006. The volumetric ratio of total emitted magma (intruded in dikes + erupted) to the contraction of the reservoir (rv) is 9.3, consistent with pressure recovery by gas exsolution in the small, shallow modeled magma reservoir. We derive a modified analytical expression for rv, accounting for changes in reservoir volume induced by gas exsolution, as well as eruptive volume. By using the precise magma composition, we estimate a magma compressibility of 1.9-3.2 109 Pa-1 and rv of 6.5-10.1. From a normal-stress change analysis, we infer that intrusions in 2010 could have encouraged the ascent of magma from a deeper reservoir along an ~N45E orientation, corresponding to the strike of the rift transfer zone structures and possibly resulting in the 2011-2012 intrusion. The intrusion of magma to greater distances from the summit may be enhanced along the N45E orientation, as it is more favorable to the regional rift extension (compared to the local volcanic rift zone, trending N155E). Repeated dike intrusions beneath Nyamulagira's SSE flank may encourage intrusions beneath the nearby Nyiragongo volcano.
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