[Autoimmune hepatitis triggered by nitrofurantoin: A rare drug-induced toxicity]. / Hépatite auto-immune induite par la nitrofurantoïne : une complication rare à connaître.

INTRODUCTION: Nitrofurantoin is a commonly used drug which can have liver and pulmonary adverse effects. Among hepatic nitrofurantoin-induced adverse effects, autoimmune hepatitis is a rare complication which must not be mistaken as a toxic hepatitis. CASE REPORT: We report an 86-year-old woman who presented with acute hepatitis after a 3-month course of nitrofurantoin administration for urinary tract infections. She reported a previous hepatitis after treatment by nitrofurantoin twenty years before. Biological analysis showed polyclonal hypergammaglobulinemia, positive test for antinuclear antibodies and smooth muscle antibodies. Finally, liver histology showed lymphocytic infiltration, marked necrotic and inflammatory activity consistent with the diagnosis of autoimmune hepatitis. Nitrofurantoin was discontinued. Outcome of autoimmune hepatitis was good with corticosteroids and azathioprine but two months later, the patient died from a refractory global heart failure. CONCLUSION: Nitrofurantoin-induced autoimmune hepatitis is a severe condition which must be systematically discussed in patients taking nitrofurantoin who present with acute hepatitis. Hypergammaglobulinemia is an easily obtained blood marker, which can suggest this diagnosis. Treatment relies on nitrofurantoin eviction, corticosteroids and sometimes azathioprine. Outcome is usually favorable.

Role of protein kinases in the prolactin-induced intracellular calcium rise in Chinese hamster ovary cells expressing the prolactin receptor.

There is still only limited understanding of the early steps of prolactin signal transduction in target cells. It has been shown that prolactin actions are associated with cell protein phosphorylation, Ca2+ increases, and so on. However, the link between the activation of kinases and calcium influx or intracellular Ca2+ mobilization has not yet been clearly established. Chinese hamster ovary (CHO) cells, stably transfected with the long form of rabbit mammary gland prolactin receptor (PRL-R) cDNA were used for PRL-R signal transduction studies. Spectrofluorimetric techniques were used to measure intracellular calcium ([Ca2+]i) in cell populations with Indo1 as a calcium fluorescent probe. We demonstrate that, although protein kinase C activation (PMA or DiC8) caused a calcium influx in CHO cells, prolactin-induced PKC activation was not responsible for the early effect of prolactin on [Ca2+]i. Activation of protein kinase A (PKA) or protein kinase G did not modify [Ca2+]i and inhibition of PKA pathway did not affect the prolactin response. In the same way, phosphatidylinositol-3 kinaseinhibition had no effect on the prolactin-induced Ca2+ increase. On the other hand, tyrosine kinase inhibitors (herbimycin A, lavendustin A, and genistein) completely blocked the effect of prolactin on [Ca2+]i (influx and release). W7, a calmodulin-antagonist, and a specific inhibitor of calmodulin kinases (KN-62), only blocked prolactin-induced Ca2+ influx but had no significant effect on Ca2+ release. Using pharmacological agents, we present new data concerning the involvement of protein phosphorylations in the early effects of prolactin on ionic channels in CHO cells expressing the long form of PRL-R. Our results suggest that, at least in the very early steps of prolactin signal transduction, serine-threonine phosphorylation does not participate in the prolactin-induced calcium increase. On the other hand, tyrosine phosphorylation is a crucial, very early step, since it controls K+ channel activation, calcium influx, and intracellular calcium mobilization. Calmodulin acts later, since its inhibition only blocks the prolactin-induced Ca2+ influx.

Distinct cytoplasmic regions of the prolactin receptor are required for prolactin-induced calcium entry.

Two cytoplasmic regions of the prolactin (PRL) receptor are well documented for their participation in PRL signal transduction, the membrane proximal box 1 and the COOH-terminal region. In order to study the role of these regions in PRL-induced Ca2+ increase, we use Chinese hamster ovary (CHO) cells stably transfected with mutated PRL receptor cDNA. These cells express the long form of PRL receptor deleted from box 1 (CHO Delta1 cells) or the 141 amino acids of the COOH-terminal region (CHO H3 cells). The patch-clamp technique in "whole-cell" configuration and microfluorimetric techniques were used singly or in combination. Data obtained for these cells were compared with those we have recently published using CHO cells expressing the wild-type long form of the PRL receptor (CHO TSE32). In contrast to CHO TSE32 cells, exposure of CHO Delta1 or H3 cells to PRL (0.05-50 nM) did not modify [Ca2+]i. We have previously shown that the PRL-induced calcium influx via voltage-insensitive, Ca2+ channels was due to the activation of tyrosine kinase-dependent K+ channels that hyperpolarize the CHO TSE32 cell membrane (hyperpolarization-driven Ca2+ influx). Therefore, two events are involved in PRL-induced Ca2+ changes (i) JAK2-activation of K+ channels and (ii) intracellular messenger-opening of Ca2+ channels. In CHO Delta1 cells, PRL (0.05-50 nM) neither hyperpolarized the membrane potential nor stimulated the JAK2-dependent K+ current, confirming the pivotal role played by box 1/JAK2 in the PRL-induced activation of K+ channels. However, when these cells were voltage-clamped below the resting membrane potential, application of 5 nM PRL resulted in an increase in Ca2+ influx. Therefore, box 1/JAK2 was not involved in the opening of these Ca2+ channels. In CHO H3 cells, 5 nM PRL activated the K+ current and hyperpolarized the membrane potential without any effect on [Ca2+]i. Moreover, PRL was also ineffective on CHO H3 cells voltage-clamped below the resting membrane potential. Therefore, the COOH-terminal region is involved in the production of the intracellular messenger that opens voltage-independent Ca2+ channels. We conclude from these findings that box 1 and COOH-terminal regions are both needed for PRL-induced Ca2+ changes.

Changes in striatal immediate early gene expression following neonatal dopaminergic lesion and effects of intrastriatal dopaminergic transplants.

To evaluate the functional integration of neonatal dopaminergic transplants within host brain we studied the postsynaptic effects induced by their stimulation by following the expression of immediate early genes c-fos, c-jun and egr-1. This study was conducted nine months after the intrastriatal implantation of embryonic mesencephalic neurons to rat pups having sustained a unilateral lesion of the nigrostriatal dopaminergic system. We examined whether, when challenged with d-amphetamine: (1) dopaminergic grafts transplanted into the previously denervated neonatal neostriatum lead to a normal activation of postsynaptic striatal neurons in term of immediate early genes activation; and (2) whether this activation is related to the action of the dopamine released from the grafts using a dopaminergic D1 antagonist. Following a mild stress-injection of saline-c-fos expression was high in the lesioned neostriatum when compared with control animals. This effect was only partially counteracted by a pre-treatment with the D1 antagonist SCH 23390, but was abolished by the graft. Administration of d-amphetamine increased c-fos expression in the neostriatum and the globus pallidus of the control group. This activation was partially blocked by the lesion. The transplant reversed the effect of the lesion and, moreover, led to a c-fos over-expression in the dorsolateral neostriatum and the globus pallidus. These overcompensations positively correlated with the abnormal rotation induced by d-amphetamine in the same animals. Pre-treatment with SCH 23390 blocked the effect of d-amphetamine on c-fos expression in control and grafted animals. Similar results were found for egr-1 but not c-jun expression. It is concluded that the neonatal lesion of the nigrostriatal dopaminergic pathway, in contrast to the adult-stage lesion, modifies the reactivity of c-fos in the neostriatum to stress, presumably in relation with compensatory reorganizations occurring following the neonatal lesion. Grafts made into neonates, when challenged with amphetamine, induce an abnormal c-fos expression which can predict the degree of overshoot observed for rotation activity. This over-expression, which depends upon the stimulation of D1 receptors, indicate an abnormal activation of postsynaptic target cells by the grafts.