Species differences in the hepatic effects of inducers of CYP2B and CYP4A subfamily forms: relationship to rodent liver tumour formation

Abstract

1. Phenobarbitone and related compounds induce hepatic microsomal cytochrome P450 (CYP) 2B forms (mediated by the constitutive androstane receptor), whereas peroxisome proliferators induce CYP4A forms (mediated by the peroxisome proliferator-activated receptor alpha) in rats and mice.

2. A number of non-genotoxic CYP2B and CYP4A inducers have been shown to produce liver tumours in rats and mice.

3. The hepatic effects of CYP2B and CYP4A inducers are reviewed and evaluated with respect to their established modes of action for rodent liver tumour formation and species differences in response. While CYP2B and CYP4A inducers stimulate replicative DNA synthesis in rodent liver, they do not appear to be mitogenic agents in human hepatocytes.

4. Epidemiological studies have demonstrated that phenobarbitone and rodent peroxisome proliferators do not increase the incidence of liver tumours in humans.

5. It is concluded that rodent CYP2B and CYP4A inducers do not pose a hepatocarcinogenic hazard for humans.

Keywords::

• Cytochrome P450
• phenobarbitone
• peroxisome proliferators
• constitutive androstane receptor
• peroxisome proliferator-activated receptor alpha
• rodent liver tumours
• mode of action
• species differences

Acknowledgements

This paper is dedicated to the memory of Professor Gordon G. Gibson. The author is proud to have known Gordon for many years and to have had the opportunity to collaborate with him in a number of research publications and one monograph on hepatic peroxisome proliferation. The author also greatly enjoyed working with Gordon to organize residential meetings for the UK Drug Metabolism Group. Gordon was an excellent scientist, with a great sense of humour, and was always a source of inspiration to his co-workers and PhD students. He will be remembered for his many contributions to toxicology, which have included studies on the CYP4A subfamily and other aspects of hepatic peroxisome proliferation and investigations on the regulation and induction of human hepatic CYP3A4.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.