Effect of pretreatment with pregnenolone-16 alpha-carbonitrile and protein-free diet on the metabolism and carcinogenicity of dimethylnitrosamine.

Abstract

Pretreatment with protein-free diet (PFD) or pregnenolone-16 alpha-carbonitrile (PCN) markedly reduces th toxicity of dimethylnitrosamine (DMN) in rats. PFD causes a shift in DMN metabolism form liver to kidney with a consequent increase in the incidence of kidney tumours. The present study was designed to evaluate the effect of PCN on the carcinogenicity and metabolism of DMN. After pretreatment with PFD, PCN or a combination of both, adult female Wistar rats received a single i.p. dose (60 mg/kg) of DMN. Animals pretreated with PFD and PFD + PCN developed a similar incidence of kidney tumours (83-85%) after a mean survival time of 357 and 396 days, respectively, Animals pretreated with PCN alone had a 50% incidence of renal tumours after a mean survival time of 672 days. This correlates with the initial extent of DMN-induced methylation of kidney DNA. Concentrations of 7-methylguanine and O6-methylguanine were highest and very similar in PFD- and PFD + PCN-pretreated rats, whereas in PCN-conditioned animals the extent of base methylation was 38% lower. Extrarenal tumours, in particular large cystic cholangiomas of the liver, were most frequent in PCN-pretreated rats, probably due to their longer survival time. In contrast to animals pretreated with either PCN or PFD, hepatic DNA methylation was markedly reduced (54-60%) in animals pretreated with both PFD and PCN.