Drug-Induced Hepatotoxicity

Abstract

This chapter aims at discussing the consequential effects of drug-induced hepatotoxicity on man. The liver carries out drug detoxification among other roles, but sometimes, drug toxicity can occur caused by either medication overdose or imbalance drug metabolic reactions (Phase 1 & 2), resulting in the formation of reactive (toxic) metabolites (electrophilic compounds or free radicals) that binds covalently to hepatocytes, leading to liver injury/diseases like acute and chronic hepatitis, cholestasis, steatosis among others. Mitochondrial dysfunction, oxidative stress and lipid peroxidation are some of the mechanisms of liver injury. Furthermore, drug hepatotoxicity results in hepatocellular, gastroenterological, cholestatic as well as immunological disorders. The clinical manifestations of drug toxicity arise from the abnormalities observed in liver’s biochemical and molecular indicators. Our findings, revealed that in the event of liver injury, liver function indices like aspartate and alanine aminotransferases, ALP (alkaline phosphatase) and gamma glutamyl transferase (GGT) activities, intracellular calcium (Ca2+) and lipid peroxidation increases whereas indices of oxidative stress such as glutathione and its allies, catalase and superoxide dismutase activity deplete. At molecular level, the gene expression levels of Bcl-2 mRNA and microRNA genes (miR-122, 192 and 194) reduces while mitochondrial genes (MMP-2 and MMP-9) overexpresses. Since drug abuse is deleterious to human health, therefore, adherence to doctors’ prescription guidelines should be followed.

1. Introduction

The liver is a reddish-brown multifunctional organ that lies beneath the diaphragm in the abdomen’s right upper quadrant and overlies the gallbladder. It performs varieties of biological and metabolic functions, but one significant of them is xenobiotic metabolism/detoxification, in which exogeneous lipophilic xenobiotics (drugs and herbal supplements) are converted to hydrophilic compounds via biochemical processes catalysed by cytochrome P₄₅₀ enzyme systems. The metabolic products obtained are then actively transported by hepatocyte transporter proteins into the plasma or bile for excretion by the kidney or gastrointestinal tract [1, 2]. However, sometimes, these xenobiotics produce reactive (or toxic) metabolites or electrophiles that bind covalently to hepatocytes, resulting to changes in protein conformation, DNA mutation or induce lipid peroxidation respectively, thereby leading to hypersensitivity reaction or liver necrosis. This is known as drug-induced injury (or hepatogenous poisoning, toxic-liver disease, chemical-driven injury). This situation often leads to hospitalisation and/or liver transplantation, depending on the magnitude of the liver injury [3]. There are over 1000 hepatotoxic agents available, however, drugs account for about 20–40% of the cases associated with liver failure/injury [4]. Notably, there are two categories of drug-induced liver injury (DILI) namely: intrinsic (or pharmacological) and idiosyncratic DILI respectively. Intrinsic DILI, refer to a form of liver toxicity caused by a drug in a projectable and dose-dependent manner (e.g. acetaminophen). In this circumstance, liver injury sets-in after an elevated concentration of the drug is attained. On the other hand, idiosyncratic DILI (which occurs relatively), is a non-projectable, non-dose-dependent response to drug and differs in the period of latency (e.g. Trovafloxacin and Troglitazone). It is worthy of note, that approximately 75–80% cases of idiosyncratic reactions end up in death or liver transplantation and as such precautionary measures should be observed in the use of drugs [5, 6]. The dreadful incidences of DILI can be checked by creating drug pharmacovigilant awareness, in which cases of adverse side effects after drug administration should be withdrawn or stopped abruptly to avoid further harm to the body. Besides the harmful effects of acetaminophen (APAP) overdose that has been well documented, studies provide us with wide spectrum of drug inducible agents like, Atypical antipsychotic (AAP), D-galactosamine ((D-GalN)), N-nitrosodiethylamine (NDEA), thioacetamide, Anti- Tuberculosis Drugs (ATD), Anti- Retroviral Drugs (ARDs), Antimalarial Drugs, NSAIDs (Non-Steroidal Anti-inflammatory Drugs), azacytidine, to mention but a few [3]. Therefore, this chapter focuses on discussing the mechanism of action and toxicological implications of drug-induced hepatotoxicity of the aforementioned drugs to human health.

2. Drugs and their role in hepatotoxicity

2.1 Paracetamol

As much as there are several analgesic drugs consumed by man as pain killer agents, paracetamol seems to be the commonly used and contains acetaminophen - the active ingredient, which has been shown to be well-tolerated in prescribed dose but in the event of overdose, liver damage occurs. This is because, acetaminophen metabolism catalysed by cytochrome P₄₅₀ enzymes in the liver produces N-acetyl-p-benzoquineimine (NAPBQI) – a highly reactive (toxic) intermediate metabolite [7]. In the normal sense, this metabolite gets detoxified by glutathione conjugation in phase II reaction. Nevertheless, during acetaminophen’s overdose, a high concentration of the toxic metabolite is produced, and thus overwhelms the detoxification process, leading to hepatocellular necrosis. Reports have shown that liver injury caused by this metabolite can be reduced by the administration of acetylcysteine - a precursor of glutathione, by scavenging the toxic metabolite from the system [8].

2.2 Atypical antipsychotic (AAP)

Antipsychotic drugs are detoxified via the cytochrome-P₄₅₀ system in the phase 1 and phase 11 reactions. In its metabolism, the enzyme known as mono-oxygenase converts the drugs into less toxic metabolites through hydrolysis, oxido-reduction and dealkylation processes. However, sometimes, the phase products may display high level of toxicity, hence, phase 11 reaction becomes inevitable. The phase II reaction mainly involves a biochemical process called conjugation reaction which makes use of glucuronic acid, sulphate, acetate, amino acids and glutathione to convert phase 1 products to a more body friendly form and subsequently for excretion. Many antipsychotic drugs beside antisulpride, risperidone, and paliperidone are catabolised primarily via the CYP2D6 and CYP3A4 systems while clozapine and olanzapine use the CYP1A2 system for its drug metabolism. Experimentation shows that antipsychotic drugs potentially damages liver cells through three mechanisms (i) By increasing bile secretion and excretion leading to cholestasis which relates to immune-mediated hypersensitivity (a typical mechanism of chlorpromazine) (ii) Accumulation of toxic or reactive intermediates (or metabolites) that eventually attacks liver cells (iii) By Increasing the risk of metabolic idiosyncratic syndrome leading to high risk of non-alcoholic fatty liver diseases which is typical of olanzapine and clozapine. Indiscriminate consumption of antipsychotic drugs presents some clinical manifestations (or side effects) and this can be encapsulated into four categories namely:

1. Hepatocellular disorder in which hepatic bio-indicators such as aminotransferases, ALP (alkaline phosphatase) and γ-glutamyl transferase (GGT) activities as well as the levels of albumin and total bilirubin are found to increase significantly in the serum.

2. Gastrointestinal disorders ranging from fatigue, appetite loss, excruciating pains in the liver region and epigastric discomfort

3. Cholestasis and steatosis like coloured stool

4. Immunological or hypersensitivity disorders including eosinophilia, anthralgia, rashes, acute liver failure (ALF), auto-immune diseases among others [9, 10].

2.3 D-galactosamine (D-GalN)

Galactosamine, one of the commonly used experimental model for hepatotoxicity study in animals, is an amino sugar derivative found majorly as glycoprotein in living cells. In addition, it forms a component of some hormonal systems like Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) respectively. Biochemical investigation into the hepatotoxic effect of D-galactosamine revealed that it induces liver damage by interfering with the products of galactosamine metabolism via Leloir pathway of galactose metabolism. Firstly, galactosamine is transformed to galactosamine-1-phosphate (Gal-1-P) catalysed by galactokinase while the second phase involves the conversion of galactosaminr-1-phosphate to Uridine diphosphate-galactosamine (UDPG) by galactose uridyltransferase. At low substrate specificity, UDPG inhibits the activity of UDP-galactose-4¹-epimerase, thereby causing a significant accumulation in the hepatic cells and others like UDP-N-acetylglucosamine and UDP-N-acetyl galactosamine with corresponding depletions of uridine triphosphate (UTP), uridine diphosphate (UDP), uridine monophosphate (UMP) as well as uridine diphosphate-glucose (UDP-Glu) and uridine diphosphate-galactose (UDP-Gal), respectively. The outcome of this process then causes the loss of intracellular Ca²⁺ homeostasis, inhibits hepatocyte ATP metabolism and hepatitis which invariably affects cell membrane, inhibits mRNA, protein and nucleic acid biosynthesis. These effects increase protein gene (p53) expression and decreases Bcl-2 mRNA levels in the liver. It is noteworthy, that the hepatoxic action of galactosamine is effective when in combination with lipopolysaccharide (GalN/LPS). This combination induces the Kupffer cells to secrete pro-inflammatory mediators that leads to liver cell apoptosis [11]. Experimental design that involves the treatment of animals with D-GalN alters albumin mRNA, glucose-6-phosphatase, histone-3 mRNA, alpha fetoprotein mRNA (αFP mRNA), gamma-glutamyl transpeptidase (GGTP) expressions. Furthermore, it also upregulates expression of tumour nuclear factor (TNF-α mRNA) that has activity of necrotic factor-kappa B (NF- κB10) and alter membrane cofactor protein (MCP-1) level in serum. Also, serum ALT and AST activities increases substantially [12, 13].

2.4 N-nitrosodiethylamine (NDEA)

N-nitrosodiethylamine (NDEA), is a member of the nitrosamine family and are found in various foodstuff and underground water with high nitrate level. It has hepatocarcinogenic property by yielding adducts of DNA carcinogen in the liver and induces hepatic cancer. NDEA’s mechanism of hepatic damage is such that after treatment, it stimulates increase in liver mitochondrial transitional permeability (MTP), leading to increase hydrogen peroxide (H₂O₂) production, resulting in peroxidative stress [14, 15]. Alternatively, cytochrome P₄₅₀ activates NDEA, generating reactive electrophilic molecules capable of increasing oxidative stress and liver cytotoxicity and carcinogenicity [16].

2.5 Thioacetamide

Thioacetamide (TAA), is a white crystalline, organosulfur compound with high affinity for water and alcohol. It is chemically designated as C₂H₅NS and generally classified as class 2B human carcinogenic agent. NDEA exhibits wide range of relevance such as serve as sulphide source in the synthesis of compounds (organic and inorganic), controls the deterioration of orange fruits (fungicidal role), precipitates cadmium sulphide from acidic solutions, drug development, pesticide production, serve as cross-linking agent but to mention a few. However, scientific reports documented that long-term oral consumption of TAA causes liver cell adenomas, cholangiomas and hepatocarcinomas as well as affects protein, nuclei acid synthesis and GGTP activity. The bio-transformation of TAA via oxidative bioactivation in the liver microsomes catalysed by flavin-containing mono-oxygenases (FMOs) and cytochrome P450 systems produce two toxic metabolites. Firstly, TAA is catalysed by thioacetamide-S-oxygenase to form a reactive intermediate, thioacetamide-S-oxide (TAASO) adduct through oxidation process, which then induces hepatocytic oxidative stress, resulting to increase in nucleoli and Ca²⁺ concentrations as well as inhibit mitochondrial activity, thereby leading to hepatotoxicity with a resultant effect of centrilobular necrosis. However, the action of CYP2E1 inhibitors (such as 4-methylpyrazole and diallyl sulphide) and TAA, block TAASO toxicity in a relative and absolute manner respectively. The second phase of metabolism involves the conversion of TAASO to thioacetamide-S-S-dioxide (TAASO_{2 -} a reactive species) by the action of thioacetamide-S-oxide-S-oxygenase and then covalently binds with protein and nucleic acid causing hepatotoxicity with consequential effect of liver damage/injury [17, 18]. The characteristic validation of the hepatotoxic effect of TAA includes decrease in microRNA gene expression (miR-122, miR-192 and miR-194) and increase in AST and ALT activities, mitochondrial membrane protein gene expression (MMP-9 and MMP-2) as well as myeloperoxidase, interleukin-10 (IL-10) and tumour nuclear factor (TNFα) respectively [19, 20, 21].

2.6 Acetylaminofluorene (AAF)/DEN

This is a fluorine derivative compound with carcinogenic tenacity. Its incorporation in diet and subsequent administration induces increased incidences of liver and urinary bladder carcinomas in animal model. Acetylaminofluorene, a by-product of diethyl nitrosamine (DEN) initiates carcinogenesis by increasing reactive oxygen species (ROS) production and facilitate hyperproliferation [22]. Acetylaminofluorene metabolism by cytochrome P₄₅₀ produces metabolites like 2-aminofluorene (AF), 2-glycoloylaminofluorene (2-GAF), N-hydroxy-2-acetylaminofluorene (NH-2-AAF), 2-acetylaminofluoren-3-,-7-,-9-ol (3-, 7-, 9-hydroxy-AAF) and 2-acetylaminofluoren-9-one (AAF-9-one) respectively and exhibits different toxicity pathway. For instance, N-hydroxy-2-acetylaminofluorene and AAF binds covalently at Carbon - 8th positions in guanine; causing single strand breaks in DNA with resultant effect of severe apoptosis. Sometimes, AAF exposure increases expression of genes implicated in p53-signalling pathway, mRNA genes [encode mitochondria drug resistance proteins (Mdr1b, Mrp1 and Mrp3)] and microRNA genes respectively, thereby resulting in apoptosis [23, 24, 25]. Studies showed that at small dose of 2-AAF for long (2.24 or 22.4 mg/kg, 3 times/week for 31 days) or high dose (448 mg/kg BW, i.g., 5 days/week for 8 weeks) produces maximum hepatocellular carcinogenesis through AAF- DNA adducts [26, 27]. Interestingly, lower dose of 2-AAF (50 mg/kg BW, i.p.) was reported to increase lipid peroxidation, deplete GSH level while the activities of glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferase (GST) were significantly reduced [28].

2.7 Anti- tuberculosis drugs (ATD)

Anti-tubercular drugs are the most auspicious prescription medication used for the treatment of cases of tuberculosis - an infectious disease with high mortality rate [29]. However, long- term administration of anti-tubercular drugs like rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (first line anti-tubercular drugs), significantly increase hepatotoxicity and induces liver injury in mammals [30]. The mechanism that precipitates anti-tubercular drug’s liver damage maybe unclear, nevertheless, studies show significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. Furthermore, lipid peroxidation, intracellular calcium (Ca²⁺) level and CYP₄₅₀2EI activity also increases while GSH level, GPx and catalase activities decreases [31]. Recently, research shows that acetylators generate high level of acetylated drug which undergo further metabolism to yield other toxic intermediates which causes liver disruption, for instance, Isoniazid acetylation by N-acetyltransferase (NTA2) enzyme produces mono-acetyl hydrazine (MAH) that increases liver toxicity [32]. Notably, polymorphism at gene loci of NTA2, CYP2E1 and GST (detoxifying enzymes) modulate the activities of these enzymes and hence increases the risk of hepatotoxicity [33]. Studies have shown some administrable dose regimen of anti-tubercular drugs that can be used for biochemical evaluation, for example, intraperitoneal administration of 50 mg/kg BW of isoniazid, 100 mg/kg BW of rifampicin and intragastric administration of 350 mg/kg BW of pyrazinamide respectively. Also, when they are in combined form such as INH and RIF as well as INH, RIF and PZA induces hepatotoxicity. This observation was in agreement with previous work as reported by [34] that daily oral administration of isoniazid (15 mg/kg BW), rifampicin (20 mg/kg BW) and pyrazinamide (35 mg/kg BW) in combined form for 45 days, increases malondialdehyde level (MDA).

2.8 Anti- retroviral drugs (ARDs)

The therapeutic action of highly active antiretroviral drugs (HAART) like Protease inhibitors (PI), non-Nucleoside reverse transcriptase inhibitors (nNRTI) and Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI) used in the management of human immunodeficiency virus (HIV) undergo various pathways, nonetheless, their adverse effects are targeted/localised at the hepatic cells [35, 36]. Take for example, all anti-retroviral therapy-native (ART-naïve) like atazanavir or ritonavir and NRTIs (such as zidovudine or didanosine) alongside N-Apostolova Efavirenz (nNRTI) causes hepatic mitochondrial dysfunction and acute mitotoxic effect and oxidative stress respectively [37, 38]. Furthermore, administration of 50 μM of Efavirenz (EFV) can activate the activities of caspase-3 and caspase −9, trigger apoptotic mitochondrial intrinsic pathway and directly inhibit mitochondrial complex 1 subunit (MC1s) expression [39, 40]. The therapeutic efficacy of antiretroviral drugs is seen when used in combinations such as nNRTI and NRTIs but reports have documented that this combination produces deleterious effects on the mitochondria and also cause hepatic steatosis [41]. Another typical mechanism of action of some antiretroviral drug like stavudine (NRTI) is its ability to arrest cell cycle in growth phase (G1 phase) through upregulation of cyclic-dependent kinase inhibitor (CDKN2A) as well as p21 genes and inhibiting mitochondrial DNA replication [42].

2.9 Anti-malarial drugs

Amodiaquine (an anti-malarial drug) hepatotoxic effect is achieved in humans when it is being oxidised by liver microsomes and peroxidases, produces iminoquinone, (a reactive metabolite) which binds to proteins irreversibly, causing direct liver toxicity by disrupting the hepatocyte function [43].

2.10 Anti-hyperlipidemic drugs

This class of drugs act mainly by hepatocellular or mixed reactions and rarely by cholestatic reaction. The Niacin and Statin are the commonly used drugs in the treatment of hyperlipidemic conditions, however, they have potential to induce liver injury. Studies revealed that the administration of Lovastatin and Simvastatin in animal model (rabbits or Guinea pig) resulted in hepatocellular necrosis while Atorvastatin produced a mixed pattern of liver injury. It is noteworthy, that Simvastatin in combination with other drugs like flutamide, troglitazone and diltiazem gives a more pronounced hepatic effect and this has been attributed to the drug–drug interaction mechanism [1].

2.11 Non-steroidal anti-inflammatory drugs (NSAIDs)

The liver damaging effects of NSAIDs like acetylsalicylic acid ranges from elevated ALT, AST and ALP activities to acute cytolytic, cholestatic or mixed hepatitis as well as increases in bilirubin and prothrombin time. The mechanistic action of NSAID-induced hepatotoxicity is unclear but both intrinsic (Aspirin and phenylbutazone) and idiosyncratic (Ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin) reactions have been documented [44]. Suggestively, hypersensitivity and metabolic aberrations are thought to responsible for liver injury. Unlike hypersensitivity reactions that are characterised by considerable anti-nuclear factor or anti-smooth muscle antibody titres as well as lymphadenopathy and eosinophilia, metabolic aberrations are caused by genetic polymorphisms, altering susceptibility to variety of drugs [45]. Diclofenac hepatotoxicity in humans and rats, for example, is linked to mitochondrial ATP synthesis impairment and the production of N-5-dihydroxydiclofenac (active metabolites), which causes cytotoxicity. Also, diclofenac-induced liver injury results in mitochondrial transition permeability (MTP), causing ROS formation, protein thiols production, mitochondrial swelling and oxidation of NADP⁺ (Nicotinamide adenine dinucleotide phosphate) respectively [45].

2.12 Anti-hypertensive drug

This anti-hypertensive drug called methyl dopa metabolises in the liver by Cytochrome P₄₅₀, however, the oxidative reaction of methyl dopa by CYP₄₅₀ produces superoxide anions (free radicals) to a reactive quinone or semi-quinone that binds tightly to the hepatic cells causing liver injury such as acute/chronic hepatitis and cholestasis with clinical evidence of elevated activities of ALT, AST and ALP respectively in the blood system [1].

2.13 Azacytidine drug

Azacytidine (or Azacitidine), is a pyrimidine nucleoside analogue of cytidine which is metabolised to a triphosphate molecule in the intracellular domain and then introduced into the RNA and DNA molecule firmly held together covalently by DNA methyltransferase 1(DNMT 1) - an enzyme that adds methyl to DNA molecule at the carbon 5 position of cytosine. Azacitidine has an anticancer effect but at low doses, it inhibits DNA methylation resulting in its deactivation leading to DNA hypomethylation shortly after cell division in the absence of DNMT1. The antineoplastic activity of this drug comes from its hypomethylation, leading to tumour suppressor gene (TSG) reactivation which is rapidly lost in myelodysplastic syndrome (MDS) – a disorder associated with clonal haematopoietic stem cell, caused mainly due to ineffective cellular maturation with side effects as peripheral blood cytopenia and abnormalities in functional blood cell. The cytotoxic effect of azacytidine is achieved when the product of its phosphorylation is incorporated into RNA molecule, thereby leading to an elevated level of CDKN2B - a gene that encodes the protein p15 (a cell growth inhibitor responsible for myeloid differentiation as well as tumour suppression) in their bone marrow [46, 47].

2.14 Acetylcholinesterase inhibitors

Administration of tacrine (a reversible cholinesterase inhibitor) in the treatment of Alzheimer disease, gives rise to an elevated ALT activity in the bloodstream, inferring that there is disruption in the integrity of the hepatocytes. Tacrine’s mechanism of liver toxicity may be probably due to the inhibition of cholinesterase activity, resulting in the stimulation of cholinergic coeliac ganglion sensory (or afferent) sympathetic pathway, in which blood constricts, leading to impaired perfusion of the sinusoids and reperfusion injury-mediated by ROS [1].

Despite the basic biochemical indicators discussed above that are associated with drug-induced hepatotoxicity, recent studies have further identified other indicators and these are represented in Table 1 as shown below:

Drug-induced hepatotoxicity	Biomarkers of Liver toxicity	References
Acetaminophen (APAP)	Upregulation of mRNA expression of IL-10, IL-36, HO-1, TNFα, MT 1 and 2 and MMP 12 genes.	[48]
D-Galactosamine	Increase in the expressions of NLRP3, NF-kBp65,, IL-6, IL-1β and TNFα genes.	[49]
N-nitrosodiethylamine (NDEA)	Increase MDA level and decrease SOD, CAT, GST, GR, GPx activity.	[50]
Thioacetamide (TAA)	Increase in Anti-PLT Ig level, Increase in the expression of TNFα, HMGB-1 and IL-6 genes. Increase in AST and ALT activity.	[51]
2-Acetylaminofluorene (2-AAF)	Overexpression of iNOS, COX-2, NF-KB, PCNA genes. Increase in xanthine oxidase (XO) activity. Decrease in the activity of SOD, CAT, GST, GR and GPx. Increase in AST and ALT activity. High density of mast cell infiltration.	[52]
Anti-Tuberculosis drugs	Over-expression of NAT2, CYP2E1, ABCB1 genes. Increase in NAD and Bilirubin levels and decrease in HAT activity. Decrease in GST, SOD, CAT activity.	[53]
Anti-retroviral drugs	Increase in ABCB1 gene expression (that is c3435C > T of ABCB1) and CYPs genes (CYP2B6, CYP3A4 and CYP3A5). Increase in IL-1RN, IL-1β, IL-10, HLA-B and C and HLA-DRB1 genes. ALP activity and Total bilirubin (TBil) level increases.	[54, 55]
Anti-hyperlipidemic drugs	Increase in the expression of HLA-DRB1 and SREBP2 genes while CK and HMG-CoA reductase activities increases.	[56]

Table 1.

Some recent findings on drug-induced liver toxicity.

Abbreviations: IL (Interleukin), HO 1 (Heme oxygenase 1), TNFα (Alpha tumour nuclear factor), MT (Mitochondrial transition), MMP12 (Mitochondrial membrane permeability 12), NLRP3 (NOD-like receptor protein 3), MDA (Malondialdehyde), iNOS (Inducible nitric oxide synthase), COX 2 (Cyclo-oxygenase 2), NTA2 (N-acetyltransferase 2), HAT (Histone acetyltransferase), CYP (Cytochrome), ABCB1 (ATP binding cassette B1), NAD (Nicotinamide adenine dinucleotide), HLA (Human leucocyte antigen), CK (Creatinine kinase), HMG-CoA (Hydroxylmethylglutaryl Coenzyme A), anti-PLT (anti-platelet), SOD (Superoxide dismutase), CAT (Catalase), GST (Glutathione-S-transferase), GR (Glutathione reductase), GPx (Glutathione peroxidase), ALP (Alkaline phosphatase), HMGB1 (High mobility group box protein 1), SREBP2 (Sterol regulatory element binding protein 2).

3. Conclusions

Drugs primarily serve as therapeutic agents in the treatment and management of various diseases, but over dependent or illicit consumption of drugs, results in hepatotoxicity which confers a detrimental effect on the liver’s architecture and functions respectively. Our findings showed that drug-induced hepatotoxicity can cause liver inflammation (associated with excruciating pains), liver transplantation (economically burdensome) as well as death. As a result of these frightening effects outlined above, we hereby conclude that doctor’s prescription guideline should be adhered to strictly, indiscriminate use of illicit drugs should be discouraged while regulatory bodies and law enforcement agencies should be empowered to prosecute drug offenders promptly.

Acknowledgments

The expertise of Professor Iheanacho Kizito, Department of Biochemistry, Federal University of Technology, Owerri is well appreciated.

Conflict of interest

The authors declare no conflict of interest in this work.