Mitochondrial disruption in isolated human monocytes: an underlying mechanism for cadmium-induced immunotoxicity.

Cadmium (Cd) is an immunotoxic metal frequently found in the environment. The in vitro study undertaken here evaluated the immunotoxic effects of Cd in isolated human peripheral blood monocytes (hPBM). The results of the studies of exposures to varying doses of Cd (0, 0.1, 1, 10, and 100 µM, as cadmium dichloride [CdCl2]) for 3, 6, 12, 24, 48, and 72 hr showed the test agent was cytotoxic to the cells in time- and concentration-related manners. Thereafter, using only those doses found to not cause extreme cell lethality a 48-hr period, the impact of 0.1 or 1 µM CdCl2 on the cells was evaluated. Functionally, CdCl2 treatment led to time- and concentration-related decreases in hPBM phagocytic activities as well as in the ability of the cells to form/release cytokines (including tumor necrosis factor [TNF]-α and interleukin [IL]-6 and -8). The CdCl2 also led to significantly decreased ATP production (in part, via inhibition of mitochondrial complexes I and III) as well as in mitochondrial membrane potentials (MMP) and oxygen consumption rates (OCR; associated with parallel increases in cell lactate production) in the cells. In addition, CdCl2 treatment resulted in significant increases in mitochondrial membrane fluidity (MMF) and cell unsaturated fatty acid content. Based on the results here, one might conclude that some of the effects that arose during the CdCl2-induced dysfunction of the isolated hPBM (i.e. changes phagocytic activity, cytokine formation/secretion) could have evolved secondary to CdCl2-induced disruptions of hPBM cell bioenergetics - an effect that itself was a culmination of an overall toxicity from CdCl2 upon the mitochondria within these cells.

Association between MDR1 polymorphisms and XELIRI and XELOX chemoresistance in Saudi patients with colorectal cancer.

Multidrug resistance member 1 (MDR1) is located on chromosome 7 and encodes P-glycoprotein, which is universally accepted as a drug resistance biomarker. MDR1 polymorphisms can alter protein expression or function, which has been previously reported to associate with various types of malignancies, such as colorectal cancer (CRC). Therefore, the present study aimed to determine the effects of MDR1 polymorphisms on drug responses of Saudi patients with CRC. DNA samples were obtained from 62 patients with CRC and 100 healthy controls. Genotypes and allele frequencies of MDR1 single nucleotide polymorphisms (SNPs) G2677T and T1236C were determined using the PCR-restriction fragment length polymorphism procedure. The results showed no significant differences in the genotype distribution and allele frequency of T1236C between patients with CRC and controls. However, G2677T was found to serve a highly significant role in protecting against the progression of CRC. In addition, none of the genotypes in SNPs T1236C and G2677T was found to affect chemoresistance to XELIRI and XELOX. In conclusion, although T1236C in the MDR1 gene is not associated with CRC risk, G2677T protects against the development of CRC. Neither of the MDR1 SNPs tested were associated with the risk of chemoresistance. Therefore, these two SNPs cannot be used as molecular markers for predicting drug response in patients with CRC.