Hexachlorobutadiene nephrotoxicity

Davis ME. 1984. Changes of hexachlorobutadiene nephrotoxicity after piperonyl butoxide treatment. Toxicology 30 217-225. 

MacFarlane M, Foster JR, Gibson GG, et al. 1989. Cysteine conjugate [3-lyase of rat kidney cytosol Characterization, immunocytochemical localization, and correlation with hexachlorobutadiene nephrotoxicity. Toxicol AppI Pharmacol 98 185-197. 

There are no specific treatments for reducing the body burden following absorption of hexachlorobutadiene. As discussed in Section 2.3, there is extensive reabsorption and enterohepatic recirculation of biliary metabolites, which are thought to play a major role in the nephrotoxicity of the... 

Absorption, Distribution, Metabolism, and Excretion. Data are available on the pharmacokinetics of hexachlorobutadiene in animals by the oral route, but not in humans. There are no data in humans or animals on exposures to hexachlorobutadiene by the inhalation or dermal routes. Because of the key role of the liver in producing the metabolites which are responsible for the nephrotoxicity of this compound, knowledge of the pharmacokinetics of inhalation and dermal exposures would be valuable. Oral studies reported the presence of the enzymes responsible for the glutathione conjugation reaction and the subsequent formation of derivatives in the liver, intestines, and kidney. 

A study is being conducted by R.G. Schnellmann (University of Georgia) for the National Institute of Environmental Health Sciences to evaluate the mechanism of nephrotoxicity of halocarbons, including hexachlorobutadiene. The mechanism of how metabolites alter proximal tubular cellular physiology to produce toxicity is being investigated, with particular emphasis on the effects of metabolites on mitochondria (CRISP 1993). 

Jaffe DR, Hassall CD, Brendel K. 1983. In wVoand in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J Toxicol Environ Health 11 857-867. 

Another example of a glutathione conjugate responsible for toxicity is the industrial chemical hexachlorobutadiene discussed in chapter 7. The diglutathione conjugate of bromobenzene is believed to be involved in the nephrotoxicity after further metabolic activation (chap. 7, Fig. 7.31). 

The nephrotoxicity of bromobenzene (see chap. 7) and possibly 4-aminophenol is also believed to be due to the cysteine conjugates of the quinone or quinoneimine, respectively. Biliary excretion and reabsorption from the gut and delivery to the kidney is a crucial part of this process as it is with hexachlorobutadiene (chap. 7). 

A variety of halogenated alkanes and alkenes such as hexachlorobutadiene, chlorotrifluoro-ethylene, tetrafluoroethylene, and trichloroethylene (Fig. 7.28) are nephrotoxic. Studies have shown that metabolic activation is necessary for toxicity, but this does not involve cytochromes P-450. Thus, hexachlorobutadiene (HCBD) is a potent nephrotoxin in a variety of mammalian species, and the kidney is the major target. 

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

Little information is available on the acute toxicity of hexachlorobutadiene in humans. Recent physiologically based pharmacokinetic models suggest an order of magnitude lower activation of reactive nephrotoxic metabolics in humans compared to rats. 

ATP is uncoupled from electron transport. Other compounds affect mitochondrial function by inhibiting the electron transport chain at one or more specific sites, such as the toxic metabolite of MPTP which inhibits complex I (see Chapter 7). The toxic metabolite of hexachlorobutadiene is believed to be nephrotoxic due to inhibition of mitochondria function in the proximal tubular cells. 

---