Hepatotoxic potential

Silver EH, McComb DJ, Kovacs K, et al. 1982. Limited hepatotoxic potential of acrylonitrile in rats. Toxicol Appl Pharmacol 64 131-139. 

Xu, J.J., Diaz, D. and O Brien, P.J. (2004) Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chemico-Biological Interactions, 150, 115—128. 

Are Reactive Metabolite Trapping and Covalent Binding Studies Reliable Predictors of Hepatotoxic Potential of Drug Candidates ... 

Kutob, S.D. Plaa, G.L. (1962) A procedure for estimating the hepatotoxic potential of certain industrial solvents. Toxicol, appl. Pharmacol.. 4, 354-361... 

Underlying liver disease can cause diagnostic confusion, e.g. the alcoholic patient receiving antituberculosis drugs. It is wise to measure liver function tests before starting treatment with any drug which has documented hepatotoxic potential. 

Petasites species have hepatotoxic potential, owing to the presence of pyrrolizidine alkaloids, which are covered in a separate monograph. Extracts of Petasites hybridus (blat-terdock, bog rhubarb, butterbur, butterdock) contain ht-tle in the way of these alkaloids (31). Butterbur has been used to treat allergic rhinitis and asthma and in the prevention of migraine. 

Tussilago farfara (coltsfoot) has hepatotoxic potential owing to the presence of pyrrolizidine alkaloids (see separate monograph). 

Coumarin has hepatotoxic potential in man, when taken in daily doses of 25-100 mg (1). Bile-duct carcinomas have been reported to occnr in rats fed coumarin, but the correctness of this diagnosis has been seriously criticized. 

Most of the members of the Crotalaria (rattlebox) species contain pyrrolizidine alkaloids, such as crotaline and monocrotaline, and therefore have hepatotoxic potential (18). These alkaloids are covered in a separate monograph. 

A 34-year-old woman developed toxic hepatitis after taking kava-kava (10). Ultrasound showed an enlarged echogenic Uver, and histology showed centrUobular necrosis and periportal inflammation. After withdrawal of the kava the changes resolved completely. This case iUustrates the high hepatotoxic potential of kava-kava. 

Kava has been associated with toxic Uver damage in six cases reported from Switzerland (12). In one patient, the Uver damage was so extensive that Uver transplantation became necessary. Histological data from four patients were consistent with an allergic mechanism. In several cases, other medications with hepatotoxic potential had been taken concurrently. Symptoms generaUy occurred at between 3 weeks and 4 months and involved daily doses that contained kavapyrones 60-210 mg. Most instances involved acetone extracts. The leading kava extract, Laitan, was subsequently withdrawn from the Swiss market. 

Mistletoe is sometimes assumed to have hepatotoxic potential, based on a case report of hepatitis due to an herbal combination product claimed to have had mistletoe as one of its ingredients (3). However, the allegation that mistletoe was the probable cause of the illness has been rightly criticized, inter alia because the botanical material was not authenticated. The incriminated product also contained skullcap, which is hepatotoxic. 

Peters TS. Do preclinical testing strategies help predict human hepatotoxic potentials Toxicol Pathol. 2005 33(1) 146-154. 

Additional safety concern A time-dependent inhibitor may need to be further studied to define its hepatotoxic potential, as a number of time-dependent P450 inhibitors are found to cause idiosyncratic hepatotoxicity. 

Additional safety concern Enzyme inducers may need to be further evaluated for their hepatotoxic potential, as a large number of enzyme-inducing drugs are found to cause severe hepatotoxicity. 

Rashed MS, Streeter AJ, Nelson SD. Investigations of the N-hydroxylation of 3 -hydroxyacetanilide, a non-hepatotoxic potential isomer of acetaminophen. Drug Metab Dispos. 1989 17(4) 355-359. 

Alcohol appears to at least add to the hypnotic effect of kava in mice, and was also observed to increase the lethality of kava (37). These findings may be of importance because some Australian Aboriginal populations now frequently consume kava with alcohol. Concomitant use of barbiturates, melatonin, and other psychopharmacological agents might potentiate the effects of kava as well (38). The hepatotoxic potential of kava (27) also raises concerns about concomitant alcohol use. 

Kostrubsky, V.E., Strom, S.C., Hanson, J., Urda, E., Rose, K., Burliegh, J., Zocharski, P., Cai, H., Sinclair, J.F. and Sahi, J. (2003) Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats. Toxicological Sciences, 76, 220-228. 

Hepatic Effects. The hepatotoxic potential of PCB mixtures is well-documented in animals by oral and other routes of exposure. The spectrum of possible hepatic effects in animals is broad and includes microsomal enzyme induction, liver enlargement, increased serum levels of liver enzymes and lipids, and histopathologic alterations that progress to fatty and necrotic lesions and tumors. The findings of human studies, however, are not as obvious. Many of the human studies involving worker and other populations with high body burdens of PCBs report associations between PCBs and hepatic indices such as liver... 

Myoclonic syndromes Myoclonic seizure syndromes are usually treated with valproic acid. Clonazepam can be effective, but the high doses required cause drowsiness. Lamotrigine is also reported to be effective in myoclonic syndromes in children. Felbamate has been used adjunctively with the primary drugs but has hematotoxic and hepatotoxic potential. 

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