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Cl
H Cl
Cl
CYP2E1
chloroform H Cl
O2 Cl
CYP2E1 dichloromethyl radical
Cl lipid membranes
HO Cl
Cl
trichloromethanol CHCl 2
phospholipid adduct
HCl low affinity pathway
O
2x Nu: H 2O
O
Cl Cl
phosgene CO2
Nu Nu
HCl HCl
formation of this strong electrophile causes adduction of renal cell proteins while
also reacting with cellular phospholipids. The protein targets for phosgene are
poorly characterised although nuclear histone proteins are likely targets in renal
epithelial cells. While similar routes of chloroform bioactivation can occur in both
liver and kidney, the possibility that noxious metabolites formed in liver are exported
to the kidney is suggested by some studies.
6.8.2.2 Trichloroethylene
One of many nephrotoxic substances within the broad haloalkene class of reagents,
1,1,2-trichloroethylene is a widely used solvent and component of degreasing
184 6 Target-Organ Toxicity: Liver and Kidney
cytotoxicity &
mutagenicity HO OH
oxalic acid
KIDNEY
Fig. 6.12 For a small molecule, trichloroethylene generates a complex array of metabolites in
vivo, some of which are shown here. While the prevailing pathway of oxidative metabolism likely
causes liver injury, kidney damage is mediated by thiol metabolites formed during metabolic pro-
cessing of S-glutathione conjugates. See Lash et al. (2000) and Guengerich (2005) for more details
6.9 Conclusion 185
Strongly nephrotoxic compounds are widely distributed within the plant kingdom.
Over the past decade, significant progress was made in solving the contribution of
weed-derived nephrotoxicants to renal nephropathy and tumourigenesis that was
long epidemic to the Balkans – a topic to be addressed in Chap. 8 (Sect. 8.7.2).
Other episodes of human nephrotoxicant exposure arise via contamination of agri-
cultural products with moulds – with particular concern focussed upon citrinin, a
nephrotoxic mycotoxin produced by Penicillium, Aspergillus and Monascus mould
strains. Monascus strains have found extensive use in China as a source of food
dyes. Other citrinin-producing moulds cause problems during the production of
cereal crops such as corn, wheat, rice, oats and barley.
Studies of citrinin nephrotoxicity are subject to some variability depending on
the experimental species used, but long-standing rodent studies indicate strong
potential to induce proximal tubular necrosis and deterioration of brush border
membranes. Although citrinin undergoes oxidative metabolism, the parent com-
pound can directly induce apoptotic cell death and oxidative stress. Since citrinin-
producing moulds often produce another potent nephrotoxic mycotoxin, ochratoxin
A, distinguishing the proximal tubular injury caused by each toxicant is difficult.
Ochratoxin A has received extensive attention due to its ability to induce hepatic
tumours as well as malignant renal tumours.
6.9 Conclusion
This chapter has explored how chronic and acute exposure to toxicants can cause
organ-selective injury to specific body organs. Due to the importance of such injury
to the pharmaceutical and chemical industry, special research attention has been
devoted to chemicals that damage the two main excretory organs, the liver and kid-
ney. A tendency to damage these organs is viewed with special concern during the
development of new medicines, and it is unsurprising that the history of
186 6 Target-Organ Toxicity: Liver and Kidney
pharmaceutical innovation is littered with the corpses of failed drugs that caused
unwanted nephrotoxicity or, more commonly, hepatotoxicity. The development of
sensitive predictive tools allowing early detection of compounds with these rogue
properties poses an ongoing challenge to the toxicology community.
To reiterate the point made in Sect. 6.1, due to space constraints within an intro-
ductory volume, this chapter was unable to explore important target-organ toxicity in
other tissues (e.g. CNS, lungs, heart or reproductive organs). Interested readers seek-
ing insight into other target toxicities should consult comprehensive toxicology texts
cited in the Chap. 2 reading list. In the following chapter, attention is given to chemi-
cally induced toxicity within the developing child, a topic of increasing concern in
the wake of rising contemporary awareness of the role of the intrauterine environ-
ment in dictating the lifelong health of mammalian species including humans.
Going Further
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