The role of cytochrome P450 enzymes in carcinogen activation and detoxication: an in vivo-in vitro paradox

TY - JOUR

T1 - The role of cytochrome P450 enzymes in carcinogen activation and detoxication

T2 - an in vivo-in vitro paradox

AU - Reed, Lindsay

AU - Arlt, Volker M

AU - Phillips, David H

PY - 2018/7/3

Y1 - 2018/7/3

N2 - Many chemical carcinogens require metabolic activation via xenobiotic-metabolising enzymes in order to exert their genotoxic effects. Evidence from numerous in-vitro studies, utilising reconstituted systems, microsomal fractions and cultured cells, implicate cytochrome P450 enzymes as being the predominant enzymes responsible for the metabolic activation of many procarcinogens. With the development of targeted gene disruption methodologies, knockout mouse models have been generated that allow investigation of the in-vivo roles of P450 enzymes in the metabolic activation of carcinogens. This review covers studies in which five procarcinogens representing different chemical classes, benzo[a]pyrene (BaP), 4-aminobiphenyl (4-ABP), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AaC) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been administered to different P450 knockout mouse models. Paradoxically, while in-vitro studies using subcellular fractions enriched with P450 enzymes and their cofactors have been widely used to determine the pathways of activation of carcinogens, there is evidence from the in-vivo studies of cases where these same enzyme systems appear to have a more predominant role in carcinogen detoxification, rather than activation.

AB - Many chemical carcinogens require metabolic activation via xenobiotic-metabolising enzymes in order to exert their genotoxic effects. Evidence from numerous in-vitro studies, utilising reconstituted systems, microsomal fractions and cultured cells, implicate cytochrome P450 enzymes as being the predominant enzymes responsible for the metabolic activation of many procarcinogens. With the development of targeted gene disruption methodologies, knockout mouse models have been generated that allow investigation of the in-vivo roles of P450 enzymes in the metabolic activation of carcinogens. This review covers studies in which five procarcinogens representing different chemical classes, benzo[a]pyrene (BaP), 4-aminobiphenyl (4-ABP), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AaC) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been administered to different P450 knockout mouse models. Paradoxically, while in-vitro studies using subcellular fractions enriched with P450 enzymes and their cofactors have been widely used to determine the pathways of activation of carcinogens, there is evidence from the in-vivo studies of cases where these same enzyme systems appear to have a more predominant role in carcinogen detoxification, rather than activation.

U2 - 10.1093/carcin/bgy058

DO - 10.1093/carcin/bgy058

M3 - Review article

C2 - 29726902

SN - 0143-3334

VL - 39

SP - 851

EP - 859

JO - Carcinogenesis

JF - Carcinogenesis

IS - 7

ER -