ABSTRACT:Irinotecan hydrochloride (CPT-11) is a potent anticancer drug that is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), and other metabolites in liver. The disposition and gastrointestinal toxicity of irinotecan exhibit a wide interpatient variability. Here, we examined the contribution of an organic aniontransporting polypeptide, OATP1B1 (OATP-C), which transports a variety of drugs and their metabolites from blood to liver in humans, to the hepatic disposition of irinotecan, SN-38, and its glucuronide conjugate (SN-38G) by using HEK293 cells stably transfected with SLCO1B1*1a (OATP-C*1a) coding wild-type OATP1B1. We further examined the effect of single nucleotide polymorphisms in OATP1B1 by measuring uptake activity in Xenopus oocytes expressing OATP1B1*1a and three common variants. In all cases, transport activity for SN-38 was observed, whereas irinotecan and SN-38G were not transported. Moreover, SN-38 exhibited a significant inhibitory effect on OATP1B1-mediated uptake of [ 3 H]estrone-3-sulfate. Among the variants examined, OATP1B1*15 (N130D and V174A; reported allele frequency 10-15%) exhibited decreased transport activities for SN-38 as well as pravastatin, estrone-3-sulfate, and estradiol-17␤-glucuronide. This study is the first to yield evidence that OATP1B1 is involved in the hepatic disposition of SN-38 and that genetic polymorphisms of OATP1B1 may contribute to the known interpatient variability in disposition of irinotecan.

The cytokine leukaemia inhibitory factor (LIF) is up-regulated in glial cells after injury to the peripheral and central nervous systems. In addition, LIF is required for the changes in neuropeptide expression that normally occur when the axons of sympathetic and sensory neurons are transected. We investigated whether LIF is also necessary for the initial inflammatory response that follows mechanical injury to the sciatic nerve and cerebral cortex of adult mice. We find that inflammatory cell infiltration into crushed sciatic nerve is significantly slower in LIF knock-out (KO) mice compared with wild-type (WT) mice. Similarly, the microglial and astroglial responses to surgical injury of the cortex are significantly slower in LIF KO mice compared with WT mice. Consistent with these in vivo results, LIF is chemotactic for peritoneal macrophages in a microchamber culture assay. Thus, LIF is a key regulator of neural injury in vivo, where it is produced by glia and can act directly on neurons, glia and inflammatory cells. We also find that the initial inflammatory response to cortical injury is diminished in interleukin (IL)-6 KO mice. Surprisingly, however, the inflammatory response in LIF-IL-6 double KO mice is very similar to that of the single KO mice, suggesting that these cytokines may act in series rather than in parallel in this response.

These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.

Because some users develop depigmentation after the use of melanogenesis-inhibiting products containing the quasi-drug ingredient Rhododenol, Japanese Dermatological Association (JDA) established a Special Committee on the Safety of Cosmetics Containing Rhododenol on July 17, 2013 and management guide for dermatologists has been updated on the website in order to delineate the diagnostic criteria for Rhododenol-induced leukoderma and provides a broad guide for standard treatment based on current knowledge. This guide is produced on the basis of the guide (version 7) updated on June 20, 2014 in the website. Rhododenol-induced leukoderma refers to depigmentation of varying severity that develops after the use of cosmetics containing Rhododenol, mainly at the site of use. In most cases, repigmentation of part or all the affected area is evident after discontinuation. Histopathologically cellular infiltration around the hair follicles and melanophages are present in most cases. The number of melanocytes in the lesion is declined but not totally absent in most cases. Rhododenol itself is a good substrate for tyrosinase, resulting in the formation of Rhododenol metabolites (e.g., Rhododenol quinone). Melanocytes are damaged by Rhododenol metabolites during the subsequent metabolic process. The continued use of cosmetics containing Rhododenol thus induces tyrosinase activity-dependent cytotoxicity in melanocytes in the epidermis at application sites, resulting in decreasing the amount of melanin produced by melanocytes; the addition of some other factor to this process is believed to subsequently cause the decrease or disappearance of melanocytes themselves from the epidermis.

We have developed a novel method that uses a microfilter mask to produce ultraviolet-induced DNA lesions in localized areas of the cell nucleus. This technique allows us to visualize localized DNA repair in situ using immunologic probes. Two major types of DNA photoproducts [cyclobutane pyrimidine dimers and (6-4) photoproducts] were indeed detected in several foci per nucleus in normal human fibroblasts. They were repaired at those localized sites at different speeds, indicating that DNA photoproducts remain in relatively fixed nuclear positions during repair. A nucleotide excision repair protein, proliferating cell nuclear antigen, was recruited to the sites of DNA damage within 30 min after ultraviolet exposure. The level of proliferating cell nuclear antigen varied with DNA repair activity and diminished within 24 h. In contrast, almost no proliferating cell nuclear antigen fluorescence was observed within 3 h in xeroderma pigmentosum fibroblasts, which could not repair either type of photolesion. These results demonstrate that this technique is useful for visualizing the normal nucleotide excision repair process in vivo. Interestingly, however, in xeroderma pigmentosum cells, proliferating cell nuclear antigen appeared at ultraviolet damage sites after a delay and persisted as late as 72 h after ultraviolet exposure. This result suggests that this technique is also valuable for examining an incomplete or stalled nucleotide excision repair process caused by the lack of a single functional nucleotide excision repair protein. Thus, the technique provides a powerful approach to understanding the temporal and spatial interactions between DNA damage and damage-binding proteins in vivo.