Elucidation of dibenzo[a,l]pyrene and its metabolites as a mammary carcinogen: A comprehensive review

The general mechanism of cancer includes the metabolism of carcinogens to highly electrophilic metabolites capable of binding to DNA and other macromolecules, thereby initiating the cells. As the carcinogenesis mechanism is quite complex where diverse cellular mechanism(s) are involved in cancer promotion and progression, it is challenging to elucidate various underlying mechanisms. The intense research to study the diverse nature of cancer initiation and development with the associated risk factors and modulators has resulted in innumerable molecular and cellular markers specific to different cancer types. Almost all the exogenous compounds entering the cells are metabolized by enzymes of phase I and phase II. During biotransformation of any pro-carcinogens and other xenobiotics, the activation of phase I and suppression of phase II enzymes are required to exert their mutagenic, toxic, or carcinogenic effect. Metabolic activation, detoxification, cellular proliferation, programmed cell death, angiogenesis, and metastasis have been involved in target-specific pathways leading to oncogenic mechanisms elucidation. The interaction of parent xenobiotics with a particular target can either positively, negatively, or neutrally influence their respective cellular pathways. In the study, biotransformation by CYP450 isozymes, detoxification by GST (glutathione S-transferase) and NAT (N-acetyltransferase) isozymes, DNA adduction formation, and (dibenzo[a,l]pyrene) DBP-mediated cell proliferation have been comprehensively reviewed.

The influence of the SULT1A status – wild-type, knockout or humanized – on the DNA adduct formation by methyleugenol in extrahepatic tissues of mice

DNA adduction by methyleugenol was nearly fully dependent on the expression of SULT1A enzymes in mouse liver, caecum and kidney. It was independent of SULT1A in stomach.

Bioactivation and DNA adduction as a rationale for ochratoxin A carcinogenesis

Ochratoxin A (OTA) is a para-chlorophenolic mycotoxin produced by strains of Aspergillus and Penicillium that is widely found as a contaminant of improperly stored food products. The toxin is a potent renal carcinogen in rats, especially male, and has an implicated role in the etiology of Balkan endemic nephropathy and its associated urinary tract tumours. Although the mechanism of OTA-mediated tumour formation is not fully understood, and represents a hotly debated topic, bioactivation and subsequent DNA adduction through covalent attachment of electrophilic OTA species remains a viable mechanism for OTA-mediated carcinogenesis. In this paper we outline the established chemistry for the bioactivation of chlorophenol carcinogens and demonstrate how this chemistry relates to the bioactivation of OTA. From this basis it is predicted that OTA will form a benzoquinone electrophile following activation by cytochrome P450 enzymes and radical species following activation by enzymes with peroxidase activities. These electrophiles react preferentially with deoxyguanosine (dG) to form benzetheno adducts and C8- dG adducts, respectively. Analysis of OTA-mediated DNA adduction using the 32P-postlabelling method correlates with OTA chemistry and adduct spots derived from the quinone electrophile are generated following activation by cytochrome P450, while a C8-OTA adduct is formed following activation of OTA by peroxidase enzymes. These same adduct spots are also produced in animal (rat and pig) and human tumoral kidney tissue. This model for OTAmediated carcinogenesis is consistent with established structure-activity relationships for covalent attachment of OTA analogues and OTA toxicity. The model also provides a rationale for the synergistic effect observed for OTA in the presence of the mycotoxin citrinin and for the sexual differences observed in rat carcinogenesis where the male is particularly susceptible to OTA-mediated tumour formation.