Risk assessment of d-limonene: an example of male rat-specific renal tumorigens.

摘要: The naturally occurring food constituent d-limonene has been found to cause tumors at high doses only in the kidney of male rat association with development hyaline droplet nephropathy. In contrast, neither nor associated nephropathy have female rats or mice much higher doses. Adult produce large quantities a specific low-molecular-weight protein liver, which is known as alpha 2U-globulin (alpha 2U-g). With administration sufficient rats, this accumulate excessively P2 segment cells renal proximal tubules, resulting formation manifestation overload. Hyaline accumulation first stage unique sequence nephropathic lesions (also 2U-g nephropathy), including granular casts outer medulla and linear mineralization papilla. mechanism underlying appears be reversible binding chemical subsequent prolongation its half-life tubule cell. case d-limonene, minor metabolite d-limonene-1,2-oxide shown primary species that binds reversibly 2U-g, impeding normal process lysosomal proteinase degradation 2U-g. ensuing sustained increase compensatory cell proliferation, provides putative mechanistic link tumor possibly through promotion spontaneously initiated enhanced spontaneous mutagenesis. This proposed supported by additional information, negative genotoxicity tests for oxide metabolites, experimentally verified promotion, proliferation primarily F344 but no such effects 2U-g-deficient NBR rat. does not appear possible humans since quantity type present. deduction induced are relevant human carcinogenicity hazard evaluation step risk assessment completes d-limonene. Consequently, it can concluded pose any carcinogenic nephrotoxic humans.(ABSTRACT TRUNCATED AT 400 WORDS)