Effect of chlorpromazine pretreatment on cadmium toxicity in the male Wistar (WF/NCr) rat.
A recent report has indicated that cadmium-induced testicular damage in CF-1 mice can be prevented by pretreatment with calmodulin inhibitors such as chlorpromazine (CPZ), trifluoperazine, or N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7). However, the basis of this tolerance to cadmium is unclear and has not been demonstrated in any species other than mice. Thus, we examined the effects of the calmodulin inhibitor CPZ on cadmium toxicity in male Wistar (WF/NCr) rats. A single sc injection of 25 mumol CdCl2/kg proved nonlethal over 24 h but caused the typical spectrum of testicular lesions and increases in hemoglobin content (as assessed by hemoglobin absorbance in testicular supernatant). Pretreatment with 40 mumol CPZ/kg had no effect on cadmium-induced testicular lesions but did reduce testicular hemoglobin content, while 120 mumol CPZ/kg moderately reduced the severity of testicular lesions and hemoglobin contents. CPZ pretreatment in some cases increased cadmium content in liver and reduced testicular content but had no effect on renal levels. Cadmium treatment markedly increased hepatic and renal metallothionein (MT), a metal-binding protein often associated with tolerance to cadmium. CPZ alone likewise increased hepatic MT and MT mRNA, but did not modify renal MT, renal MT mRNA, or testicular MT mRNA. In contrast to liver and kidney, testicular cadmium-binding protein (TCBP) decreased in rats exposed only to cadmium or to CPZ, while CPZ pretreatment had no further effect on cadmium-induced reductions in TCBP levels. These results indicate that, like mice, CPZ in rats can reduce the testicular toxicity of cadmium as indicated by CPZ-induced reductions in testicular vascular lesions and hemoglobin contents. However, in rats CPZ has a less dramatic effect on such cadmium-induced lesions than in mice. The CPZ-induced stimulation of hepatic MT gene expression or modification of toxicokinetics may both play roles in this acquired tolerance to cadmium.
Shiraishi
N
N
Inorganic Carcinogenesis Section, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201.
Rehm
S
S
Waalkes
M P
MP
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002104:Cadmium / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D002746:Chlorpromazine / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006454:Hemoglobins / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000737:chemistry; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D015032:Zinc / Q000378:metabolism
D001786:Blood Glucose; D006454:Hemoglobins; D015345:Oligonucleotide Probes; D002104:Cadmium; D008668:Metallothionein; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D015032:Zinc; D002746:Chlorpromazine