Gadolinium chloride reduces cytochrome P450: relevance to chemical-induced hepatotoxicity.
The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the liver from a number of toxicants that require biotransformation to elicit toxicity (i.e. 1,2-dichlorobenzene and CCl4), as well as compounds that do not (i.e. cadmium chloride and beryllium sulfate). The mechanism of this protection is thought to result from reduced secretion of inflammatory and cytotoxic products from Kupffer cells (KC). However, since other lanthanides have been shown to decrease cytochrome P450 (P450) activity, the following studies were designed to determine if GdCl3 pretreatment alters hepatic P450 levels or activity. The toxicological relevance of GdCl3-mediated alterations in P450 activity was also estimated by determining the effect of GdCl3 pretreatment on the susceptibility of primary cultured hepatocytes to CCl4 and cadmium chloride (CdCl2). Male and female Sprague-Dawley rats were given GdCl3 (i.v., 10 mg/kg). Twenty-four hours later, livers were either processed for preparation of microsomes or for primary cultures of hepatocytes. Gadolinium chloride treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by approximately 30% in males and 20% in females. In hepatocytes isolated from rats pretreated with GdCl3, the toxicity caused by CCl4, but not CdCl2 was reduced. Interestingly, when GdCl3 was administered in vitro to microsomes, there was no effect on either the microsomal P450 difference spectra or p-hydroxylation of aniline. However, when GdCl3 was incubated with isolated hepatocytes, the cytotoxicity of CCl4 (but not CdCl2) was partially attenuated. These results suggest that, in addition to its inhibitory effects on KC, GdCl3 produces other effects which may alter the susceptibility of hepatocytes to toxicity caused by certain chemicals.
Badger
D A
DA
Department of Pharmacology and Toxicology and Center for Toxicology, The University of Arizona, Tucson 85721, USA.
Kuester
R K
RK
Sauer
J M
JM
Sipes
I G
IG
D000704:Analysis of Variance; D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001711:Biotransformation; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005682:Gadolinium / Q000008:administration & dosage / Q000494:pharmacology*; D006900:Hydroxylation; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System; D005682:Gadolinium; D002251:Carbon Tetrachloride; D000815:Aniline Hydroxylase; C038958:gadolinium chloride; C023650:aniline