Based on a comparative approach using PCB isomer and congener compositions in higher animals and their food organisms, the capacity and mode of PCB metabolism in small cetaceans were studied and the following conclusions were drawn: (1) Small cetaceans can metabolize some of the lower chlorinated biphenyls and this capacity seems to be the same in all species of these animals. (2) The values of MI, an index to evaluate the capacity of PCB metabolism, showed that the metabolic capacity of small cetaceans was extremely low as compared to those of birds and terrestrial mammals. (3) The structural requirements for PCB metabolism were different in animal species, in that small cetaceans have no capacity to metabolize a group of PCBs with adjacent non‐chlorinated meta and para carbons in biphenyl rings. (4) No development of PB (phenobarbital)‐type enzymes, and a lower activity of MC (3‐methylcholanthrene)‐type enzymes were suggested in small cetaceans, which implies long‐term accumulation and possible reproductive toxicity of persistent organochlorines in these animals. The present approach should provide an important insight into the physiological responses of small cetaceans to persistent toxic chemicals.
In many patients with cancer, chemotherapy-induced severe oral ulcerative mucositis causes intractable pain, leading to delays and interruptions in therapy. However, the pain mechanism in oral ulcerative mucositis after chemotherapy has not been extensively studied. In this study, we investigated spontaneous pain and mechanical allodynia in a preclinical model of oral ulcerative mucositis after systemic administration of the chemotherapy drug 5-fluorouracil, using our proprietary pain assay system for conscious rats. 5-Fluorouracil caused leukopenia but did not induce pain-related behaviors. After 5-fluorouracil administration, oral ulcers were developed with topical acetic acid treatment. Compared with saline-treated rats, 5-fluorouracil-exposed rats showed more severe mucositis with excessive bacterial loading due to a lack of leukocyte infiltration, as well as enhancements of spontaneous pain and mechanical allodynia. Antibacterial drugs, the lipid A inhibitor polymyxin B and the TRPV1/TRPA1 channel pore-passing anesthetic QX-314, suppressed both the spontaneous pain and the mechanical allodynia. The cyclooxygenase inhibitor indomethacin and the TRPV1 antagonist SB-366791 inhibited the spontaneous pain, but not the mechanical allodynia. In contrast, the TRPA1 antagonist HC-030031 and the N-formylmethionine receptor FPR1 antagonist Boc MLF primarily suppressed the mechanical allodynia. These results suggest that 5-fluorouracil-associated leukopenia allows excessive oral bacterial infection in the oral ulcerative region, resulting in the enhancement of spontaneous pain through continuous TRPV1 activation and cyclooxygenase pathway, and mechanical allodynia through mechanical sensitization of TRPA1 caused by neuronal effects of bacterial toxins. These distinct pain mechanisms explain the difficulties encountered with general treatments for oral ulcerative mucositis-induced pain in patients with cancer and suggest more effective approaches.
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