TOXICOLOGICAL PROFILE FOR CHROMIUM - Davidborowski.com

CHROMIUM 1452. HEALTH EFFECTSand NADPH-dependent, and the rates were proportional to the amount of microsome added. In humans,the K m for chromium(VI) was one to three orders of magnitude lower than K m values in rats, although theV max was similar. This suggests that the human liver has a much greater capacity to reduce chromium(VI)than the rat liver. Also contrary to the rodent data, oxygen and cytochrome P450 inhibitors (carbonmonoxide, piperonyl butoxide, metyrapone, and aminopyrine) did not inhibit chromium(VI) reduction.These differences indicate that, in humans, cytochrome P450 does not play a significant role in thereduction process, but that other microsomal flavoproteins are responsible for reducing chromium(VI).Inhibition of flavoproteins by TlCl 3 decreased chromium(VI) reduction by 96–100%, while inhibition ofcytochrome c reductase (P450 reductase) by bromo-4'-nitroacetophenone resulted in an 80–85%inhibition of chromium(VI) reduction. Combined, these observations implicate P450 reductase, workingindependently of cytochrome P450, as a major contributor in the reduction of chromium(VI) in humanmicrosomes. These findings suggest that metabolism of chromium(VI) in rodent systems may not readilybe extrapolated to humans.Microsomal reduction of chromium(VI) can also result in the formation of chromium(V), which involvesa one-electron transfer from the microsomal electron-transport cytochrome P450 system in rats. Thechromium(V) complexes are characterized as labile and reactive. These chromium(V) intermediatespersist for 1 hour in vitro, making them likely to interact with deoxyribonucleic acid (DNA), which mayeventually lead to cancer (Jennette 1982). Because chromium(V) complexes are labile and reactive,detection of chromium(V) after in vivo exposure to chromium(VI) was difficult in the past. Morerecently, Liu et al. (1994) have demonstrated that chromium(V) is formed in vivo by using low-frequencyelectron paramagnetic resonance (EPR) spectroscopy on whole mice. In mice injected with sodiumdichromate(VI) intravenously into the tail vein, maximum levels of chromium(V) were detected within10 minutes and declined slowly with a life time of about 37 minutes. The time to reach peak in vivolevels of chromium(V) decreased in a linear manner as the administered dose levels of sodium dichromatedecreased. The relative tissue distributions of chromium(V) indicated that most was found in the liverand much lesser amounts in blood. None was detected in kidney, spleen, heart, or lung. When the micewere pretreated with metal ion chelators, the intensity of the EPR signal decreased demonstrating that theformation of chromium(V) was inhibited. Reactions of chromium(VI) with glutathione produced twochromium(V) complexes and a glutathione thiyl radical. Reactions of chromium(VI) with DNA in thepresence of glutathione produced chromium-DNA adducts. The level of chromium-DNA adductformation correlated with chromium(V) formation. The reaction of chromium(VI) with hydrogenperoxide produced hydroxyl radicals. Reactions of chromium(VI) with DNA in the presence of highconcentrations of hydrogen peroxide (millimolar compared to 10 -7 to 10 -9 M inside cells) produced