Phenobarbital causes a multitude of effects in hepatocytes, including increased cell proliferation, inhibition of apoptosis and upregulation of xenobiotic and endobiotic metabolizing enzymes. In this study, the involvement of several protein kinase and phosphatase pathways on constitutive and phenobarbital-induced activities of CYP2A5, CYP2B10 and CYP1A1/2 in primary mouse hepatocytes was determined using welldefined chemical modulators of intracellular protein phosphorylation and desphosphorylation events. A 48-h treatment of the hepatocytes with 2-aminopurine, a nonspecific serine/threonine kinase inhibitor, elicited dose-dependent increases in both basal and phenobarbital-induced CYP2A5 catalytic activity (assayed as coumarin 7-hydroxylation), the maximal induction being 60-fold greater than the control value upon cotreatment with 1.5 mm phenobarbital and 10 mm 2-aminopurine. In contrast, phenobarbital induction of CYP2B10 (pentoxyresorufin O-deethylase) and CYP1A1/2 (ethoxyresorufin O-deethylase) activities were blocked by 2-aminopurine. Increases in CYP2A5 activity were also observed after exposure of the hepatocytes to other protein kinase inhibitors affecting the cell cycle, i.e. roscovitine, K-252a and rapamycin. Inhibitors of protein kinases A and C, as well as tyrosine kinases, did not appreciably affect CYP2A5 activity levels. The serine/threonine phosphatase inhibitors tautomycin, calyculin A and okadaic acid all reduced both basal and phenobarbital-induced CYP2A5, CYP2B10 and CYP1A1/2 activities. These results further strengthen the concept that hepatic CYP2A5 is regulated in a unique way compared with CYP2B10 and CYP1A.Keywords: CYP induction; phosphorylation; primary hepatocytes. Phenobarbital (PB), a drug that has been widely used in the treatment of epilepsy, elicits pleiotropic morphological and biochemical effects in the liver, including an increase in hepatocyte proliferation, inhibition of apoptosis, an increase in liver weight and the induction of several genes encoding enzymes involved in the metabolism of xenobiotics and endobiotics. PB is also an efficient tumor promoter in the liver [1]. A recent study showed that <30 genes are modulated by PB in the chick embryo liver, 60% of them being upregulated and 40% being downregulated [2]. One of the most striking effects of PB is the induction of cytochrome P450 (CYP) genes that encode enzymes involved in the metabolism of numerous xenobiotics and endogenous compounds [3]. The expression of several individual CYP genes in the liver, including members on the CYP1A, CYP2A, CYP2B, CYP2C and CYP3A subfamilies, is elevated by PB [4].The CYP2A5 enzyme and its human orthologue CYP2A6 metabolize a number of substrates of practical relevance. CYP2A5/6 substrates include several pharmaceuticals, such as coumarin, halothane and losigamone, as well as several toxins, such as nitrosamines, aflatoxins and nicotine [5]. CYP2A5 expression is increased in the mouse liver by a number of structurally varying compounds, including PB, pyrazole and porphyrinogenic ...

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Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREG BOLD ) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age‐matched controls (median 63y; 73% females) were scanned for MREG BOLD signal during 2018–2021. Motion effects were removed. Voxel‐by‐voxel Coefficient of Variation (CV) maps of MREG BOLD signal was calculated to examine the stability of physiological brain pulsations. Group‐level differences in CV were examined using nonparametric covariate‐adjusted tests. Subject‐level CV alterations were examined against control population Z‐score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast‐enhanced, diffusion‐weighted, fluid‐attenuated inversion recovery (FLAIR) data]. Whole‐brain mean CV was linked to short‐term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values ( n = 5, median 0.055) than surviving patients ( n = 16, median 0.028) ( p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories ( p ≤ .001). Abnormal clusters (median 1.10 × 10 5 mm 3 ) extended spatially beyond FLAIR lesions (median 0.62 × 10 5 mm 3 ) with differences in volumes ( p = .0055).

We thank Dr Turin and colleagues for their interest in our work. Their results are in line with ours: untreated hypertension associates significantly with spontaneous intracerebral haemorrhage (ICH) occurrence during the cold season.The possible effect of diabetes on seasonality of ICH is interesting. Unfortunately, Turin et al. do not offer detailed information of how they classified patients as having untreated diabetes. How should we classify a person who has received diet counselling because of high blood glucose levels? A person who has lost weight and no longer needs medication for diabetes has a history of diabetes, but does (s)he have untreated diabetes?We did not include untreated diabetes in our analyses, because it is not easy to identify reliably individuals with untreated diabetes. Therefore, we classified as diabetics only those on oral hypoglycaemic medication or insulin.Turin et al. assume that untreated diabetes might increase the risk for ICH during the cold season. However, it did not significantly predict ICH during the cold season in their analysis. Nor was drug-treated diabetes significantly associated with seasonality of ICH in our study. Consequently, the role of diabetes in association with seasonality of ICH remains unclear.