Abstract:
:Oral cocaine administration results in hepatic necrosis, increased plasma transaminase concentration, and decreased antioxidative capability, which is potentiated by lipopolysaccharide (LPS) in male CF-1 mice. Females administered the same treatment regimen display none of the hepatotoxic effects seen in their male counterparts. This study was conducted to further dissect the mechanism responsible for this gender difference in cocaine hepatotoxicity (CH) and lipopolysaccharide potentiation of CH. Male and female CF-1 mice were orally administered 20 mg/kg cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration the mice were administered 12 x 10(6) EU LPS intraperitoneally. The activity of plasma esterase (butyrylcholinesterase), the enzyme responsible for the major pathway of cocaine metabolism to nonhepatotoxic metabolites, was measured. Aminotransferase release and histological analysis were used to determine hepatotoxicity. The concentration of the hepatotoxic precursor norcocaine was measured in the plasma and liver. Regardless of treatment, males were shown to have only 30% of the plasma esterase activity displayed by females. In addition, administration of testosterone to ovariectomized females resulted in a 70% reduction in plasma esterase activity when compared with surgically unaltered females. Moreover, hepatic norcocaine was not detected in the plasma or liver of surgically unaltered female animals, while it was present in males and testosterone-supplemented ovariectomized females. These results indicate that plasma esterase activity is heavily influenced by sex hormones, predominantly testosterone, in CF-1 mice. Suppression of plasma esterase by testosterone correlates with decreased norcocaine production and is therefore responsible, in part, for the increased CH seen following oral administration with and without LPS exposure in male CF-1 mice.
journal_name
Toxicol Mech Methodsjournal_title
Toxicology mechanisms and methodsauthors
Visalli T,Turkall R,Abdel-Rahman MSdoi
10.1080/153765291009840subject
Has Abstractpub_date
2005-01-01 00:00:00pages
383-9issue
6eissn
1537-6516issn
1537-6524journal_volume
15pub_type
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