Involvement of Reactive Metabolites

The mechanism of drug-induced lupus is unknown; however, there is a large amount of circumstantial evidence to suggest that the mechanism involves a chemically reactive metabolite. In the case of procainamide, sulfonamides and sulfasalazine, acebu-tolol, and practolol, the reactive metabolite is formed by oxidation of the aromatic amine functional group (Uetrecht 1988). Acebutolol and practolol are the only two blockers that are metabolized to aromatic amines, and they are also the only two for which there are good data to support a causal relationship with a lupus-like syndrome (Wilson et al. 1978). In a similar vein, minocycline is the only tetracycline that is an aromatic amine, and it seems to be the only tetracycline that is associated with a significant incidence of a lupus-like syndrome. In the case of minocycline, the reactive metabolite seems to be a quinone imine rather than a hydroxylamine, but its formation still involves oxidation of the aromatic amine.

Hydralazine and isoniazid are hydrazine derivatives, which are readily oxidized to reactive metabolites. The exact structure of the reactive metabolite has not been proven, but it is most likely a diazonium ion intermediate (Hofstra and Uetrecht 1993). The reactive nature of propylthiouracil and penicillamine are due to the sulfur atoms. In the case of propylthiouracil, the sulfur is oxidized to several reactive species (Waldhauser and Uetrecht 1991), while the sulfhydryl group of penicillamine can react with protein without metabolic activation. The chemistry of quinidine reactive metabolite formation has not received much attention, but, on paper, it should be o-demethylated to a metabolite that is further converted to a quinone methide reactive metabolite. The phenothiazines are known to be oxidized to free radical intermediates (Kalyanaraman and Sohnle 1985), but the exact chemistry associated with the drug-induced lupus syndrome has not been demonstrated. The idiosyncratic reactions associated with anticonvulsants were believed to be due to arene oxide reactive intermediates (Spielberg et al. 1981); however, even anticonvulsants that do not have an aromatic ring have been associated with a lupus-like syndrome, and other types of reactive metabolites have been demonstrated (Ju and Uetrecht 1999).

Many other drugs are metabolized to reactive metabolites and yet are not associated with the induction of a lupus-like syndrome; however, in many cases, they do cause other types of idiosyncratic adverse reactions. There are several factors that are likely involved in determining the pattern of idiosyncratic reactions that a drug (or reactive metabolite) will be associated with. One is simply where the reactive metabolite is formed. By their very nature, most reactive metabolites will not reach significant concentrations at sites distant from where they are formed. Most drugs associated with lupus (or their hepatic metabolites) are oxidized by the myeloperoxidase system present in neutrophils and some macrophages (Uetrecht 1996). This maybe an important factor because of the importance of these cells in the immune response.

The macromolecules that are modified by the reactive metabolite are also likely to be an important determinant of a drug's ability to cause lupus, and it is unlikely an accident that drug-induced lupus is often associated with antimyeloperoxidase antibodies (Shapiro et al. 2001). As mentioned earlier, there is a clear dose dependency to drug-induced lupus, and most drugs associated with the induction of lupus are given at dosages greater than 100mg/d. In the case of procainamide, the dose can be several grams per day.

Many hypotheses have been proposed to link reactive metabolites with the pathogenesis of drug-induced lupus. It is likely that there are several different effects that contribute to the induction of lupus by drugs, and the pattern is probably different for different drugs.

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