Free radicals hepatic generation

Mercury has been shown to affect hepatic microsomal enzyme activity (Alexidis et al. 1994). Intra-peritoneal administration of mercuric acetate (6.2 mol/kg/day) once daily for 6 days or once as a single dose of 15. 68 mol/kg resulted in an increase in kidney weight and a significant decrease in total cytochrome P-450 content. The single 15.68 mol/kg injection resulted in the reduction of both microsomal protein level and P-450 content, possibly resulting from the generation of free radicals during the Hg intoxication process. 

Figure 12. ESR spectra of nitro-anion free radicals from the microsomal reduction of nitro compounds, a. Radicals from the anaerobic incubation of 2 mM nitrobenzene with an NADPH-generating system and 1.5 mg/ml hepatic microsomes b, radicals from the anaerobic incubation of 1 mM nitrofurantoin with an NADPH-generating system and 1 mg/ml hepatic microsomes. From [88,169], with permission.

In contrast, acetaldehyde and free radicals generated from ethanol metabolism can result in alcohol-induced hepatitis, a condition in which the liver is inflamed and cells become necrotic and die. Diffuse damage to hepatocytes results in cirrhosis, characterized by fibrosis (scarring), disturbance of the normal architecture and blood flow, loss of liver function and, ultimately, hepatic failure. 

Some examples of free-radicals generated by the bioactivation of drug molecules are shown in Fig. 10.31. Isoniazid is acetylated to its major metabolite acetylisoniazid, which is hydrolyzed to acetylhydrazine and isonicotinic acid (Fig. 10.31-1). Acetylhydrazine is further metabolized by the CYP2E1 to an N-hydroxy intermediate that hydrates into an acetyl radical, which can then initiate the process that leads to hepatic necrosis. Other carbon-centered radicals are formed from hydrazines such as the antihypertensive hydralazine, and thio-radicals from the ACE inhibitor captopril (Fig. 10.31-2 and -3). 

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