Benzene, cytochrome, carcinogenesis: A topic in preventive toxicology.

Benzene is a common chemical substance with confirmed toxicity to human beings. The benzene toxicity can be in either acute or chronic. Also, the carcinogenicity of benzene is confirmed. Hence, the control of benzene usage is a topic in preventive toxicology; however, this substance is still problematic in many industrialized settings. In this article, the author discusses benzene and cytochrome focusing on the carcinogenesis process. A further extrapolation on the aspects on preventive toxicology is also included.

INTRODUCTION

Benzene is a volatile aromatic substance that is widely used in industrial works. It is considered a common chemical substance leading to many toxic disorders. Both acute and chronic intoxications are described and are focused in present medicine.[1] In acute intoxication, nausea, vomiting, dizziness, headache, and death in the most severe cases are described.[23] In chronic exposure, several clinical manifestations including anemia and malignancy are mentioned.[234]

It is no doubt that a good control measure is needed for this problem. Regulation of benzene exposure becomes an important issue in occupational medicine and preventive toxicology. Indeed, several kinds of toxicities, such as hematotoxicity, hepatotoxicity, renotoxicity, neurotoxicity, and genotoxicity due to benzene exposure are described.[23] There are many studies on the toxicity of benzene with many new ones on the biomarkers and clinical biochemistry parameters alteration after exposure to benzene. Those studies are required for better understanding on the pathogenesis of benzene and further finding for preventive action.

In general toxicology, a response of human body to any intoxication can be expected. This is called detoxification system. A physiological action occurs in the liver, and the cytochrome system is an important biochemical system in human beings that responds to the toxic substance. Generally, drugs and other chemicals are usually metabolized in the liver based on the specific metabolizing enzyme system.[5] This is useful in detoxifying the toxic substance. On the other hand, the metabolites sometimes interact with cellular macromolecules leading to cellular injury and further pathological processes, including to carcinogenesis.[5] Based on the present knowledge, the pathobiological process via cytochrome system is widely described for its interrelationship to cancer development.[6] The indepth focus in genomics level is widely studied.[6] In this article, the author discusses benzene and cytochrome system, focusing on the carcinogenesis process. A further extrapolation on the aspects on preventive toxicology is also included.

Benzene, cytochrome, and carcinogenesis

It is no doubt that benzene can induce the toxicity to the exposed subjects. Similar to any toxic substances, the detoxifying of benzene via cytochrome system can be seen in normal physiology. Biologically, benzene is first metabolized via cytochrome P450 (primarily CYP2E1 in the liver).[78] The main metabolite is benzene-oxide, which can lead to the disturbance in the normal cytochrome system.[7] In vivo, benzene oxide–oxepin results in blocking one-electron oxidation by cytochrome P450 mono-oxygenase and finally leads to the formation of (E, Z)-muconaldehyde.[7] Accompanied with this process, a minor pathway leading to sym-oxepin oxide that can further repeat the mentioned process is also observed.[9] Of interest, the oxide–oxepin is the main substance that is mentioned for its DNA disturbance activity.[10] This is believed to be the primary process leading to genotoxicity and carcinogenesis.[10]

Hence, it is no doubt that there can be an interrelationship between the benzene and cytochrome. As already mentioned, the genetic mutations and polymorphisms within cytochrome system are focused as important factors leading to different responses to a toxic substance.[6] This concept can also be applied for explaining the pathobiology of benzene-induced malignancy. In a report by Ross et al., it is concluded that “Susceptibility to the toxic effects of benzene has been suggested to occur partly because of polymorphisms in enzymes involved in benzene metabolism, which include cytochrome P450 2E1.[11]”

There are many new reports focusing on cytochrome and benzene. Most of them mention the possible relationship. Several cytochromes are studied and there is no conclusion yet. The examples of studies on some important cytochromes are further discussed.

CYP4F3A

CYP4F3A is a cytochrome that is widely studied for its relationship with benzene. It is reported that both benzene and metabolites resulted in the induction of CYP4F3A and DNA-PKcs.[12] This induction can be observed both in vivo and in vitro and this is the main pathogenesis of benzene hematotoxicity as well as leukemogenesis.[12] Therefore, it is assumed that CYP4F3A determination can be a good biomarker of benzene exposure.[1213]

CYP2E1

CYP2E1 is another cytochrome that is focused on its relationship to benzene. There are many reports on CYP2E1 and benzene with different results. Most studies reported the null relationship between the polymorphic alleles of CYP2E1 and the metabolic activation of benzene,[14151617] whereas a few mentioned a strong relationship.[1819] Focusing on positive reports,[1819] the CYP2E1 FNx01 5B, FNx016, and FNx017B variants are mentioned as risk factors. However, not similar to the case of CYP4F3A, the CYP2E1 might not be a good biomarker for monitoring benzene exposure.

Other cytochromes

There are some other reports on other cytochromes and benzene. For example, a study in China reported that individuals with CYP2D6 c. 188 C/C, CYP2D6 c. 188 C/T, C/T, CYP1A1 MspIT/T, and c. 5639 T/T genotypes tend to be more susceptible to benzene toxicity.[2021]

Cytochrome and carcinogenesis of benzene: Aspect in preventive toxicology

It is no doubt that there are at least some relationships between cytochrome and carcinogenesis of benzene. Hence, there might be some applications on cytochrome determination as useful tool in preventive toxicology.

Monitoring of cytochromes’ activities can be helpful in determining the response to exposure. Higher induction of cytochrome might be the sign of high exposure. This monitoring is better than monitoring of metabolite because the monitoring of cytochrome activity is the direct measurement of response and toxicity to the human body.[2223] In addition, there is no relationship between excreted metabolite in urine and cytochrome activity.[23] The explanation is the urine metabolite level is a cross-sectional measurement without any correlation to accumulation or deterioration of organ function due to that toxic substance

Monitoring of genetic polymorphism of cytochromes can be a useful approach to judge for the risk of each individual in developing of cancer after exposure to benzene. At a same dosage of benzene exposure, one who has a risk allele might have more chance to further develop a cancer. Hence, there can be a good plan for each specific individual for decreasing his/her risk.