Chemoprevention By Isothiocyanate The In Vivo Evidence

One of the major characteristics of chemical carcinogens is their ability to act as DNA alkylating agents inducing DNA aberrations that have the potential to lead to genetic mutations. Several well-characterized carcinogens, such as benzo[a]pyrenes, nitrosamines, and aflatoxin B1, can form DNA adducts with exposed bases in double-stranded DNA (Fig. 2). The overall consequence of this is the possible impairment of DNA replication and the induction of genetic mutation. This can be especially significant if these occur in tumor suppressor genes such as p53. A possible mechanism to prevent these deleterious effects is to use dietary agents that can alter the metabolism of carcinogens and thus reduce or prevent DNA damage. Of the many dietary compounds studied, low-dose exposure to ITCs has been proven to be highly effective in preventing DNA damage and the development of cancers in animal models (reviewed in Refs. 2,7 and summarized in Table 2). Recent experiments have focused on the inhibition of tumor formation induced by several nitrosamines and polycyclic aromatic hydrocarbons found in tobacco smoke. Of the approximately by 4000 compounds identified 43 have the potential to induce tumor formation in animal models (reviewed in Ref. 63). Two of the most effective carcinogens identified were the polycyclic aromatic hydrocarbons represented by benzo[a]pyrene and the nitrosamine 4-(meth-ylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Both compounds promote tumor formation in animal models. B[a]P and NNK are also suggested to be potent initiating factors in the induction of tobacco-related human cancers. Dose-dependent inhibition by arylalkyl ITCs and their N-acetylcysteine conjugates on NNK-induced tumor formation in rodents has been widely addressed; several of these studies are summarized in Table 2 (64-74). Common to many of these studies is a reduction in the deposition and an increase in Phase II detoxification metabolites of many of these carcinogens.

Aflatoxin Cancer Mechanism
Figure 2 Metabolism, DNA adduct formation, and detoxification of the carcinogenic agents aflatoxin B1 (AFB1) and 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) in mammalian cells. (This figure is by no means comprehensive. See Refs. 90,95.)
TABLE 2 Summary of the In Vivo Chemopreventive Properties of Isothiocyanates in Rodents

Animal model

Tissue

Carcinogen

Isothiocyanate

Effect

Ref.

A/J mice

Pulmonary,

B[a]P

BITC

Inhibition

64

forestomach

A/J mice

Lung

NNK

Aromatic

Inhibition

65

ITCs

Fisher rats

Esophagus

NBMA

PEITC

Inhibition

66

ACI/N rats

Intestine

MAM

BITC

Inhibition

67

Fischer rats

Esophagus

NBMA

BITC/PBITC

No effect

68

A/J mice

Lung

NNK

PEITC

Inhibition

69

Sprague-

Mammary

DMBA

PEITC

Inhibition

70

Dawley rats

tissue

Fischer rats

Esophagus

NNK

PPITC

Inhibition

71

Fischer rats

Colon

AOM

Sulforaphane

Inhibition

85

Rats

Bladder

DEN and

BITC/PEITC

Promotion

51

BBN

Fischer rats

Bladder and

DEN

PEITC

Promotion

73

liver

A/J mice

Lung

B[a]P and

BITC/PEITC

Inhibition

74

NNK

ICN mice

Stomach

B[a]P

Sulforaphane

Inhibition

46

A/J mice

Lung

B[a]P

2BITC

Inhibition

83

BITC, benzyl isothiocyanate; PEITC, phenylethyl isothiocyanate; PPITC, phenylpropyl isothiocyanate; PBITC, phenylbutyl isothiocyanate; sulforaphane, 4-methylsulfinylbutyl isothiocyanate; AOM, azoxymethane; B[a]P, benzo[a]pyrene; DEN, 1, 2-diethylnitrosamine; DMBA, 7,12-di-methylbenzanthracene; MAM, methylazomethanol acetate; NNK, 4-(methylnitroamino)-1-(3-pyridyl)-1-butanone; NBMA, N-nitrosobenzylmethylamine.

BITC, benzyl isothiocyanate; PEITC, phenylethyl isothiocyanate; PPITC, phenylpropyl isothiocyanate; PBITC, phenylbutyl isothiocyanate; sulforaphane, 4-methylsulfinylbutyl isothiocyanate; AOM, azoxymethane; B[a]P, benzo[a]pyrene; DEN, 1, 2-diethylnitrosamine; DMBA, 7,12-di-methylbenzanthracene; MAM, methylazomethanol acetate; NNK, 4-(methylnitroamino)-1-(3-pyridyl)-1-butanone; NBMA, N-nitrosobenzylmethylamine.

PEITC and BITC, both prominent isothiocyanates in watercress, garden cress, and papaya, have been the focus of much of this attention. PEITC can inhibit tumor formation induced by NNK in both rat and mouse models but it is ineffective at inhibiting tumor formation induced by B[a]P (75-79). In contrast, BITC can inhibit tumor formation induced by B[a]P while having no inhibitory effect on NNK (79-83). These contrasting differences are currently under investigation in several laboratories, and suggest that for effective chemoprevention a combination of ITCs or other phyto-chemicals may be necessary in preventing tumor formation. Additional research also shows both PEITC and BITC can inhibit DMBA-induced mammary tumors in rats, with PEITC being additionally effective in the inhibition of N-nitrosbenzylmethylamine (NBMA)-induced esophageal tumors (66,68-72). Likewise, sulforaphane, a very potent Phase II detoxfica-

tion enzyme inducer from broccoli, can inhibit DMBA-induced tumor formation in rat mammary tissues while also showing a protective effect against azoxymethane (AZO)-induced aberrant crypt foci in rats (84,85). However, it is ineffective against B[a]P-induced lung tumor formation in A/J mice (74).

Of all the in vivo studies only a few have been conducted on human subjects, many of these being coordinated by Hecht and colleagues. In humans, it is hypothesized that PEITC prevented the metabolic activation of carcinogens to more toxic forms. During the early investigation it was demonstrated that consumption of watercress in smokers significantly increased the levels of the detoxification products of the NNK metabolite NNAL and NNAL-Gluc in the urine (86). It was suggested that this effect was either due to the inhibition of NNK metabolism by CYP450 isoenzymes or due to the induction of Phase II detoxification enzymes involved in their excretion. Follow-up studies determined the latter to be the influencing factor with data suggesting that components in watercress were inducing the phase II detoxification enzyme UDP-glucuronosyltransferase (87).

Many of the in vivo traits of synthetic isothiocyanates are also observed for the respective vegetables from which they are derived. Cabbage, brussels sprouts, and broccoli have all been shown to reduce mammary tumor formation in rats exposed to DMBA (82). More recent investigations have shown that selenium-enriched broccoli is also effective at reducing intestinal tumor formation in mice exposed to dimethylhydrazine (88). Additional studies using multiple intestinal neoplasia mice as a rodent model in which the rodents are predisposed to the development of tumors in the small and large intestine show a significant reduction in the numbers of tumors when the rodents are fed selenium-enriched broccoli (89). Whether an interaction between GSL components and methylselenocysteine (the predominant seleno- compound in plants) can occur in vivo has not been determined; however, both agents do have chemopreventive properties and such effects are feasible. Nevertheless this requires further investigation.

Aflatoxin B1 (AFB1), a potent hepatocarcinogen, is recognized by the International Agency for Research on Cancer (IARC) as a group 1 carcinogen in humans. It is generally accepted that the formation of AFB1-8,9-epoxide generated by the metabolism of AFB1 by cytochrome P450 can cause the covalent binding of the epoxide to guanine bases present in DNA. More important is the finding that AFB1 epoxide is able to induce mutations in the tumor suppressor gene p53 and K-ras oncogenes. These factors are suggested to contribute to AFB1-induced carcinogenesis (reviewed in Ref. 90). The first study showing the modulation of AFB1-DNA adduct formation by Brassica vegetables was conducted by Godlewski et al. In feeding studies GSL-containing fractions of brussels sprouts were shown to diminish the number of g-glutamyl transpeptidase foci induced by AFB1 in hepatic tissues, a marker of hepatocarcinoma (91). Additional research indicates that the consumption of brussels sprouts had a pronounced inhibitory effect on aflatoxin B1 DNA binding in rats. Rodents administered 3H-AFB1 either intraperitoneally or intragastrically, showed a 50-60% reduction in AFB1 DNA binding in hepatic tissues (92). Likewise, consumption of cabbage induced an 87% reduction of AFB1 DNA binding in weaning Fischer F344 rats (93). Associated with all three studies was a significant increase in detoxification enzyme activity in hepatic tissues. These findings could be attributed to the presence of unidentified GSL hydrolytic products in the vegetable extracts. Supporting this hypothesis is the study by Hayes et al. showing that ITCs can induce GSTA5-5, a major GST involved in the detoxification of AFB1-epoxide (94,95).

The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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