Cytotoxicity P450 induction

Portal infusion of NAPQl into rats and mice produces necrosis in the periportal region (unpublished results quoted by Nelson, 1990). Studies of cultured hepatocytes sensitized to paracetamol by the induction of cytochrome P450 by 3-methylcholanthrene have shown that paracetamol-induced cytotoxicity was dependent on ROM generation (Gerson et al., 1985). 

No induction observed The substance evaluated is not an enzyme inducer if P450 inhibitory and cytotoxic potential are eliminated as confounding factors. 

Pralavorio M, Lesca P, Rahmani R. 1998. Cytotoxic effects and induction of cytochromes P450 1A1/2 by insecticides, in hepatic or epidermal cells binding capability to the Ah receptor. Toxicol. Lett. 96/97 33-39... 

It has been well established that fatty acid metabolites of LOX and cytochrome P450 are implicated in essential aspects of cellular signaling, including the induction of apoptosis. The enzymatic and non-enzymatic products of polyunsaturated fatty acids thus control cell growth and apoptosis, and the spontaneous oxidation of polyunsaturated fatty acids gives rise to reactive aldehydes and other products of lipid peroxidation that are potentially cytotoxic and which may also signal apoptosis [102]. 

Chronic use of ethanol causes induction of a cytochrome P450 isozyme that converts acetaminophen to a cytotoxic metabolite. This appears to be the explanation for the increased susceptibility of alcoholics to hepatotoxicity with overdose of acetaminophen. The answer is (D). 

The structural characteristics of individual PCB congeners influence their induction of various P450 activities. In mammals, PCB congeners have been characterized as 3-methylcholanthrene-type inducers, phenobarbital-type inducers, or mixed-type inducers of both. AHH and EROD activities (which are preferentially catalyzed by the P450IA gene subfamily) have been induced by planar PCBs in fish and mammals and by some mono- and di-ortho analogs of planar PCBs in mammals. The mechanism of toxic action of planar and mono-ortho planar PCBs is linked to an interaction with the 2,3,7,8-TCDD (or Ah) receptor protein. But this mechanism does not account for all observed PCB toxici-ties. Toxic responses uiuelated to Ah receptor effects have been reported of PCBs 4, 28, 31, 49, 52, 84, 95, 110, 136, and 153. For example, PCB 153 is less cytotoxic than PCB 169... 

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